Exforge is a blockbuster drug sold by Novartis for lowering blood pressure that combines two medications in a film-coated tablet It contains amlodipine, a dihydropyridine-type calcium channel blocker, and valsartan, an angiotensin II receptor antagonist (ARB or A2RA); typically formulated as the benzenesulfonate salt.
Israel Patent Application No. IL 140665 titled “USE OF COMBINATION COMPOSITIONS COMPRISING VALSARTAN AND AMLODIPINE IN THE PREPARATION OF MEDICAMENTS FOR THE TREATMENT AND PREVENTION OF DIABETES ASSOCIATED WITH HYPERTENSION” relates to the drug.
In an Opposition to the Patent Application issuing, the Deputy Commissioner, Ms Jacqueline Bracha, has ruled that the combination of two active ingredients, each individually known for treating high blood pressure, into one pill for ease of dosage is not inherently inventive where the separate efficacy of the active ingredients is known, as are other two component pills for treating hypertension. Though claimed by applicants, there is no evidence of a synergy between the active ingredients. The Patent Application is therefore ruled not patentable in Israel and significant costs were awarded to Teva and Unipharm. We expect that the decision will be appealed. This decision may have a knock on effect regarding patents for the same drug abroad and may encourage Teva to proceed with at-risk launches of generic competitors in other jurisdictions.
A translation of the ruling follows:
The present application was filed in Israel on 1 Jan 2001, and is the national phase of PCT/EP1999/004842 that was filed in July 1999 and claims priority from USSN 09/113,893 that was filed on 10 July 1998.
Teva filed an Opposition on 24 March 2013 and Unipharm filed a second one a few days later on 2 April 2013. The Opposers filed their evidence together and so Ms Jacqueline Bracha, the Deputy Commissioner, saw fit to combine the two Oppositions into one proceeding.
There are three families of blood pressure lowering drugs: ARB that includes amlodipine, ACE and CCB which includes valsartan. The Application relates to the combination of amlodipine and valsartan as an oral blood pressure lowering combination drug. The basis of the Opposition is whether the claims include two drugs are taken together or one after the other. There is no argument that both drugs are independently known to lower blood pressure. The question is whether the combination is or isn’t fairly described as being a non-obvious invention having an inventive step or not.
The Opposers Claims and Evidence
The Opposers allege that the claimed patent covers taking Amlodipine and Valsartan together under a doctor’s prescription and is not restricted to a Fixed Dose Combination. Consequently, the claimed invention is directed to the clinical physician, who, at the time of filing already on occasion prescribed combinations of different known blood pressure limiting drugs. To support this allegation they submitted an Expert Opinion of Professor Zimmlichman, who, amongst other jobs, was the director of the High Blood Pressure Institute of the Wolfson Medical Center. (The Opposers also submitted an affidavit of Ms Shpungtal that related to medical prescriptions from the United States for the claimed combination of drugs. However, this affidavit was struck from the evidence in a judicial decision of the Deputy Commissioner back on 22 April 2014).
Since the active ingredients were de facto combined by the physicians of record prior to the priority date, the Opposers allege that the patent is not novel. They further claim that the combination was obvious to persons of the art from scientific articles published prior to the priority date rendering the claimed invention non-patentable. Such articles included:
- The accompanying documentation from packages of the drug Diovan
- Farsang et al. “Antihypertensive Effects and Tolerability of Candesartan Cilexetil, Amlodibine and Their Combination”, American Journal of Hypertension (1997), Vol. 10, Issue 4, Supplement 1, p.80A which advises taking an ARB drug together with Amlodibine.
- P. Prasad et al. “A Pharmacokinetic Interaction Between an Angiotensin II Receptor Blocker (Valsartan) and a Calcium Channel Blocker (Amlopipine), AJH – April 1997, Vol. 10, No.4, Part 2, p. 107A (להלן: “Prasad”), which concludes after testing for pharmacological interactions, that one can take Amlodipine and Valsartan in combination.
- Luigi Corea et al. “‘Valsartan, a New Angiotensin II Antagonist for the Treatment of Essential Hypertension: A Comparative Study of the Efficacy and Safety Against Amlodipine”, Clinical Pharmacology & Therapeutics, September 1996, p.341 which tests for side effects of the combination of the two drugs
- Dahlof et al. “The Losartan Intervention For Endpoint Reduction (LIFE) in Hypertension Study; Rationale, Design, and Methods”, American Journal of Hypertension, 1997, Vol. 10, p.705
- Bernard Waeber and Hans R. Brunner “Combination Antihypertensive Therapy: Does it Have a Role in Rational Therapy?”, American Journal of Hypertension, 1997, Vol. 10, p.131
There are additional references that the parties related to that are referenced below.
Since the Applicants claimed that the patent related to a Fixed Dose Combination (FDC) and not to the combination per se, in their response to the Counter-Statement by Applicants they submitted an Affidavit by Professor Gershon Golomb of the School of Pharmacology of the Hebrew University of Jerusalem who testified about the difficulty in combining the two drugs into one dosage. Golomb also related to the chemical structure of valsartan and its pharmacokinetic characteristics, in particular with respect to other ARB materials. In their counter-evidence, the Opposers submitted a further Expert Opinion of Professor Zimmlichman that included additional references not mentioned in the Statement of Case. In a decision of 11 January 2015, Ms Bracha ruled that these references and their citations in the counter statement should be struck from the record. (The Opposers attempted to reinstate this evidence after the parties related to them in the cross-examination of the experts).
The Opposers further alleged that Professor Bjorn Dahlof, as a clinical physician [mere empiricist? MF] is not sufficiently qualified to testify about the pharmacokinetics of valsartan. The Opposers further alleged that the Applicant has concealed evidence in that they did not bring those that at the priority date were employed by the Applicant as witnesses.
The Applicant’s evidence gave rise to their claim that there was a doubt about prescribing family CCB chemicals which includes amlodipine. The Opposers reason that there is an onus on the Applicant to substantiate this claim, referred to as “perfect storm” in Professor Dahlof’s testimony, that this was a preconception that would have deviated the average person of the art from the solution of the invention.
The opposers also claimed that the Application did not prove the efficacy in lowering blood-pressure of the claimed combination, since the Applicants did not append clinical results referred to in the Application. In the summary of the responses, Unipharm repeated its claim that the invention is for a therapeutic treatment of a person and thus contravened Section 7(1) of the Patent Law and was not patentable subject matter.
The Applicant’s Counter Case
The Applicant claims that the Patent Application relates to a dosage that combined two known materials that, when taken together, provide a surprising synergy not known at the priority date. The Applicant claims that the Application covers the pharmaceutical Exjorge [sic. Exforge is presumably meant – MF] which they manufacture and which is a very successful drug, with sales of 1.5 billion dollars a year which in itself is indicative of inventiveness. There is nothing in doctors prescribing combinations of drugs to challenge the novelty of the claimed invention since the FDC had not, at the priority date, been requested to regulate a dosage of the two drugs.
The Applicants claims that there were tens of drugs that were developed to treat high blood pressure, as is shown in Appendix 9 of the opinion of Professor Zimlichman (The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (1997). There is no doubt that treatment by a single active ingredient is not always enough, particularly long-term, and that not all drugs are equally efficient for all patients. So the recommended strategy is to combine drugs. However, not all combinations are safe and effective .
With respect to the evidence submitted, the Applicants claims that the question of inventive step is not tested from the perspective of the inventor but from that of the average person of the art, and so there was no requirement to bring the inventors as witnesses [and not doing so is not evidence of bad faith – MF]. The Applicants reason that the prior art documentation does not instruct combining amlodipin with evalsartan, and there was actually a warning not to combine them. The Applicants claims that there were many clinical trials and research programs to find the right combination of the various drugs.
The World Health Organizations (Appendix 7 to Professor Zimlichman’s opinion and the rules to clinical physicians from the WHO did not relate to the claimed combination. Furthermore, it was not a suggested research approach at that time as can be seen from Waeber (ibid).
The Applicants further claim that of all the ARB family, valsartan was the newest and had a significantly different structure form from the others. valsartan had a less significant pharmacokinetic effect from the other family members. Amlodipine was considered unsafe and there were recommendations to remove the entice CCB family from use. (It was the later ASCOT tests that were after the priority date that calmed fears). So the combination is inventive.
The Applicant emphasized that the European Patent Office EPO had upheld the patent against a similar opposition based on the same prior art documents. As to the claim of lack of utility, the Applicant noted that this contradicted the Opposers other claims and the utility is self-evident to persons of the art. Furthermore, there is no need to show utility in the application itself, and it is sufficient to demonstrate utility during the Opposition proceedings.
The issues that are contested are:
- Is the claimed invention for taking two active ingredients concurrently of for a Fixed Dose Combination?
- Dependent on the understanding given to the claims, whether the combination is novel in light of combinations of the active ingredients by physicians?
- Does the invention include an inventive step over the prior art?
- Is there sufficient proof of utility?
The claimed invention
The invention is claimed in 15 claims of which claims 1-5 relate to a medical formulation, claim 6 i-9 are Swiss type use claims and claims 10-13 are for the combination.
Independent claim 1 is as follows:
“A pharmaceutical composition for the prevention or treatment of hypertension consisting substantially of (i) valsartan, or a pharmaceutically accepted salt thereof, (ii) amlodipine, or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable carrier.”
The claims are self-explanatory. Where necessary, reference may be made to the specification, but they cannot be detached from the specification (See Appeal 235/87 Hughes Aircraft Company vs. State of Israel p.d. 44(4) 45, 67). It is also established that when construing claims, one has to be very careful:
Indeed, the explanation of a patent is not substantively different from that of any other document, and the regular rules of interpretation apply. Nevertheless, one has no be careful due to the character and strength of a patent, which effectively creates a monopoly in the market. The general approach to interpretation is that the patent should be read as a complete document in order to come to an understanding of the Applicant’s intent as it is expressed in the patent document as a whole. As Judge Asher put it in Appeal 2051/69  page 247, “it is not feasible to say that the claims should be detached from that said previously, as if they were created ex nihilo”. So one cannot read the claims detached from the specification and from that shown in the Figures.”
It is feasible that a court will construe the claims differently when considering infringement from when considering oppositions, as the purpose of the construction is different. When considering infringement, the court will construe the claims more narrowly to minimize competition, but will interpret the claims to keep the patent valid. (See paragraph 19 of 6750/10 Triplex Pal Yam LTD. vs. Plasson Ltd. 18 Dec 20146750/10 Triplex Pal Yam LTD. vs. Plasson Ltd. 18 Dec 20146750/10 Triplex Pal Yam LTD. vs. Plasson Ltd. 18 Dec 2014). In contradistinction, during opposition proceedings, the commissioner will take care not to interpret the claims too narrowly, so avoid issuing a patent from an invention that if interpreted correctly, is not patentable over the prior art. However, where the Applicant has declared a narrower interpretation, this minimizes the suspicion that at the time of alleged infringement the interpretation will be wider, because the declaration will estoppel such interpretations.
The question is essentially whether the phrase ” A pharmaceutical composition” includes taking two different drugs, one after the other. It seems that this interpretation of the Opposers is rather extreme. In a similar case where Teva opposed, Opposition to IL 153109 Teva Pharmaceuticals Ltd. vs. Merck & Co Inc. (5 Aug 201o)Opposition to IL 153109 Teva Pharmaceuticals Ltd. vs. Merck & Co Inc. (5 Aug 201o) in paragraph 4 of the decision which was upheld on appeal twice:
We will assume for good order, that when using the term pharmaceutical composition, the intention is for a medical preparation that includes the active ingredient together with usual types of additives.
Further on in paragraph 25:
My conclusion is that the correct explanation in this instance is that the claimed monopoly is for a medical preparation with instructions that relate to the dosage frequency, as is virtually always done for all medical preparations.
In this instance, we are relating to a pharmaceutical preparation that includes two active ingredients, but this does not in and of itself have a widening effect. That a composition including the two active ingredients is intended also is clear from the specification page 1a. The Opposer is correct that the specification includes other alternatives such as “combined administration”, see Page 3 of the specification, but this option is NOT claimed in claim 1.
From this, the Deputy Commissioner concludes that correct explanation is that suggested by the Applicant, that this is a single medical preparation that includes two active ingredients and a carrier as found in pharmacology.
Question of Novelty
The opposers alleged that the even if one interpreted the claims to relate to a Fixed Dose Combination (FDC), one should still conclude a lack of novelty due to previous co-prescription, the instructions to the Physician for Diovan, and the LIFE research results.
Section 4 states that:
4. An invention is deemed new if it was not published, in Israel or abroad, before the application date—
- (1) by written, visual, audible or any other description, in a manner that enables a skilled person to make it according to the particulars of the description;
- (2) by exploitation or exhibition, in a manner that enables a skilled person to make it according to the particulars thus made known.
To accept a claim of lack of Novelty, it is necessary to show that the invention is described in one document (see Appeal 235/87 Hughes Aircraft Company vs. State of Israel p.d. 44(4) 45 (pages 103-106).
Professor Zimmlichman, who provided the Opposer’s Opinion, has 31 years experience in internal medicine. In paragraph 56 of his Opinion of 22 Dec 2013, he testified that:
For these reasons, in the framework of my activities as a physician, prior to the priority date I treated patients with high blood pressure with combinations of ARB and CCB drugs.
In his Opinion, Professor Zimmlichman details that he prescribed amlodibine together with an active ARB (losteren), which is not the active ingredient valsartan that is claimed here. From here, Professor Zimmlichman did not combine the claimed ingredients and so one cannot conclude that he publicly exhibited the claimed invention before the priority date.
In his cross-examination, Dr Dahlof, the Applicant’s expert witness was asked if he had treated patients with high blood pressure with the combination of ARB and CCB (pages 18-19 of the protocol of the hearing from 4 March 2015). Dr Dahlof acknowledged that he may have prescribed such a combination but did not acknowledge prescribing the claimed combination, so one cannot conclude that he publicly exhibited the claimed invention before the priority date either.
The LIFE research results are discussed in Dr Dahlof’s Opinion, and he was also cross-examined on this. From the document and from the testimony it is clear that this research was undertaken after the priority date and that it used Losteren and not Valsartan.
The Physician’s Data Sheet for Diovan was published prior to the priority date of the Application. The Opposers focussed on paragraph 3, titled Drug Interactions which states:
“No clinically significant pharmacokinetic interactions were observed when valsartan was co-administered with amlodipine, atenolol…”
This paragraph relates to drug-drug interactions and warns the physician about using the drug together with others. Professor Zimmlichman agrees that this was its purpose (see page 131 of the protocol of the hearing of 3 March 2015).
In determining whether this earlier publication could discount novelty of the invention, the Deputy Commissioner turned to the British rulings on this question (see David Young, Antony Watson, Simon Thorley, Richard Miller “Terrell on the Law of Patents”, 1994, p. 118-119):
“To anticipate the patentee’s claim the prior publication must contain clear and unmistakable directions to do what the patentee claims to have invented…”
“The antecedent statement must, in order to invalidate the subsequent patent, be such that a person of ordinary knowledge of the subject would at once perceive and understand and be able to practically apply the discovery without the necessity of making further experiments.”
She do not consider that this Physician’s Data Sheet anticipated the claimed invention. After ruling that the claimed invention is a single combined dose it is clear that the Physician’s Data Sheet does not relate to such a single combined dose. furthermore, it is not at all clear from the data sheet if the usage of the two active ingredients was to treat patients or to test drug-drug iterations and there is no recommendation to prescribe the two drugs together or suggestion that this will be beneficial.
Does the invention include an inventive step over the prior art?
As stated in Section 5:
5. An inventive step is a step which does not, to an average skilled person, appear obvious in the light of information published before the application date in ways said in section 4.
To determine whether or not the invention is inventive, it is necessary to determine the state of knowledge in the field and the identity of who could reasonably be considered an average person of the art.
The Average Person of the Art
The Average Person of the Art is someone who would be consulted to solve the problem that the present invention addresses (see Cancellation Proceedings against IL 148492 Indigo Tabernacle Industries vs. Crown Holy Vestments Ltd (Nevo 8 March 2009).
The Opposers consider the person of the art is a treating physician and the problem is how to treat high blood pressure or diabetes related high blood pressure (see paragraph 37).
Dr Dahlof fulfils disagrees with this conclusion by Professor Zimmlichman and considers that since the issue is the formulation of a medical preparation and since treating physicians do not develop drugs or combine active ingredients, the person of the art is an expert team that includes pharmacologists and physicians, where the physician’s task is to design clinical trials and to analyze their results (see 3.2 of his opinion).
In his cross-examination, Professor Dahlof was asked and affirmed that to create the invention one required a team including a clinical physician. Professor Dahlof also clarified that during his career he had been part of such a development team (see page 158 of the protocol from 4 March 2015).
With this, the Application does not describe a particular problem of pharmacology inherent in developing a single dose that includes two active ingredients. However, one can assume that Professor Dahlof is correct that development of a medical preparation includes more than a physician’s expertise.Consequently, Ms Bracha acepts the Applicant’s assertion that the person of the art is, in this instance, a team of experts, but it appears that the essence of the invention is the choice of successful active ingredients. Such a choice will be based on clinical trials once both drugs are independently known to work, and for determining the chemical composition of the active ingredients to ensure that there is nothing preventing them being combined in a single pill.
It appears that the Opposers largely accepted this position during the proceedings, as they included an Expert Opinion from Professor Golomb who has tenure at the School of Phamacology of the Hebrew University and has expertise that enables him to testify regarding the pharmacological aspects of the invention.
in this regard, it is stressed that since Professor Dahlof is a clinical physician and NOT a pharmacologist, in accordance with his testimony, he cannot provide the full picture of average experts in the field, since had he been part of the team, he would have supplied only the clinical medical aspects of the solution. Furthermore, due to the lack of expertise of Professor Dahlof in phamacology, one has to take care when considering his statements in this field, which sometimes go beyond his expertise.
State of the Art at the Priority Date
The parties agree that:
- All the active ingredients were known at the priority date and were in use for lowering blood pressure
- The active ingredients belong to different families of drugs for lowering blood pressure: amlodipine is a CCB family member and valsartan is an ARM ftype drug
- Physicians did combine drugs to lower blood pressure, and generally selected drugs of different type in accordance with the condition of the patient and his clinical state, including other illnesses suffered
- There were various known combinations of ACE and CCB type drugs
- At the priority date, Fixed Dose Combinations were sold for treating high blood pressure
The Opposers claimed that at the priority date ACE and CCB drugs were being combined. ACE type drugs are equivalent to ARB drugs, but with fewer side effects and so it was obvious to interchange between them. Patients were being treated with combinations of ARM and CCB. Therefore it would have been obvious to combine the two presently claimed active ingredients and there were no preconceptions that taught away from combining them. The Opposers also claimed that the only dosage was a reasonable solution for the patient taking the drugs.
The Applicants claim that it is not proven that it was a known practice to combine the two families and that even if one were to select family members from the two families, it is not clear that the two specific drugs would have been chosen. They claim that there were good reasons not to prescribe amlodipine and valsartan together. They further asserted that the additional tests of inventive step such as the long-felt need and commercial success testify that the invention is patentable.
Review of the Literature
Substituting ACE materials for ARB materials
In his opinion, Professor Dahlof claimed that the ARB group were newer and were considered safer and with fewer side-effects such as coughing which was a known side-effect for ACE drugs. However, ARB drugs were considered weaker.
In B. Dahlof “Effect of angiotensin II blockage on cardiac hypertrophy and remodeling: a review”, Journal of Human Hypertension (1995), p.S37-S44), Professor Dahlof held that the ARB drugs were safer and he focused on Losartan which was more thoroughly searched in the LIFE research. It is noted that at that time, in 1995, the active ingredient Valsartan, which was later marketed as Diovan, had not yet received FDA approval.
An earlier paper from 1992 makes the assumption that the ARB drugs are not as effective as ACE, but the paper itself states that this is more of a theoretical than an empirical assumption.
Professor Dahlof also held that at that time, there was no room for such doubts and he didn’t believe them. (See Protocol from 4 March 2015). The Deputy Commissioner notes that the Applicants did not think that the ARB family members were selectively more effective than the ACE family members. In a paper dedicated to the effectiveness of valsartan, the lack of side-effects of the material compared to the coughing associated with ACE family members and the ease of taking the drug once a day were discussed. (See Suzanne Oparil et al. “The Efficacy and Safety of Valsartan Compared with Placebo in the Treatment of Patients with Essential Hypertension”, Clinical Therapeutics, vol. 18, No. 5, 1996, p.797).
Together with other researchers, Professor Dahlof published a research proposal that compared the efficiency of Telmisartan (from the ARB group) with metoprolol (from the ACE group) for patients suffering from hypertension – (Matthias G Friedrich et al. “Telmisartan Effectiveness on Left ventricular Mass Reduction (TELMAR) as assessed by magnetic resonance imaging in patients with mild-to-moderate hypertension – a prospective, randomized, double-blind comparison of telmisartan with metoprolol over a period of six months – rationale and study design”. The purpose of the research was to examine the effect of the drug on left ventricular hypertrophy, a phenomenon wherein the heart gets used to hypertension, but may increase the number of deaths from coronary related causes. The research assumed that the ARB members are more effective than ACE member at reducing LVH occcurences (Page 235): “Therefore, ARBs may be more effective in regressing LVH than ACE inhibition.”
From that above it transpires that at the time of the priority application it was widely believed by persons of the art that ARB drugs were better than ACE drugs in that they should fewer side effects. Valsartan was considered advantageous in that it had a long efficacy and needed taking only once a day.
Distrust of taking CCB drugs
The Applicant claims that in the three years prior to the submission of the patent application there was widespread panic regarding usage of CCB drugs. The distrust arose due to reports of deaths as a result of recurring heart attacks following using such drugs for reducing hypertension.
Professor Zimmlichman reported the mayhem in real-time. “Pandemonium in Calcium Blockers, Lessons for the Future, Medicine 132(III) 2 Feb 1997. in that paper, he concluded that one cannot point to a greater occurrence of coronary muscle dystrophy after taking CCB. In a further paper by Reuven Zimmlichman and Yehuda Sheinfeld titled “Drugs that Clog Arteries, Calcium and Cancer, is there a connection between them?” Medicine Volume 132(XII) 15 June 1997, the connection between CCB drugs and cancer was considered. The conclusions were unequivocal:
In summary, one can state that presently there is no evidence of the authors’ assumption, that calcium blockages increase the risk of cancer. Furthermore, the FDA’s people have considered the evidence and have not reached any operative conclusions or recommendations to change the prescription of calcium blockers and there is no basis today for any changes.
Professor Dahlof notes that even if there were doubts about using CCB drugs, this focused on short-term drugs such as nifedipine. Amlodipine, however, is not part of this family, as Professor Dahlof himself confirmed under cross-examination (Page 120 of the protocol from 4 March 2015). Furthermore, according to the Australian Medicines Handbook 1998, amlodipine is preferable to nifedipine due to recent suspicions regarding nifedipine, particularly among patients with myocardial infraction or unstable angina. This recommendation concurs with a paper by Professor Zimmlichman which stated that:
The important point that damages the scientific work of this research is the fact using nifedipine which has short-term efficacy, which is not the correct form to treat hypertension and angina. The correct treatment for these conditions is to treat with drugs that prevent calcium blockage which have a long-term effect.
The Deputy Commissioner concluded from the above that the Applicant did not succeed in proving his claim that at the priority date there was a suspicion against using amlodipine since it is a CCB family drug. Furthermore, at the priority date, amlodipine was the most widely used drug for treating hypertension, as testified by experts from both parties. (See Professor Dahlof’s testimony from 4 March 2015 on page 132, and paragraph 18 of Professor Zimmlichman’s opinion). This does not sit with the alleged apparent danger to patients treated in this manner.
In fact it was Professor Dahlof that initiated the ASCOT research wherein the monotherapy of amlodipine and atenolol (another CCB drug) was tested. Afterwards, if the monotherapy was found inadequate, the combination of amlodipine with an ACE drug and of atenolol with other drugs was to be tested. This research project started before the priority date and was focused on amlodipine. For this reason as well, one cannot accept the position that amlodipine was considered dangerous at that time.
Prior Art that Considered Combinations of Drugs from Different Groups
Just as in ASCOT the combination of amlodipine with other drugs was considered, the parties concur that at the time of filing, treatment of hypertension with combinations of drugs was commonplace. The experts even agreed that the combination wasn’t random, meaning that to combine two active drugs it is neccessary to do research that demonstrates that the combination is safe and that the effects are additive. (See Professor Zimmlichman – page 95 of the protocol from 3 March 2015). The combination of drugs was recommended by the World Health Organization for hypertension in cases where single drugs were not sufficiently effective (1993 Guidelines for the Management of Mild Hypertension). On page 400 the WHO recommend combining drugs from different families:
“Effective combinations use compounds from different drug groups. This permits the addition of different primary actions while minimizing the homeostatic compensations that limit the fall of pressure.”
It was also clarified in that publication that the combination reduces the likelihood of side-effects. However, there is no argument that the combinations recommended in the WHO publication does not include these families.
In a later publication which also considers treating hypertension by combining drugs from different families (JNC VI), it is recommended in absence of counter instructions, to start treatment with different drugs of beta blockers, although there is a list of diseases where it is advisable to dissent and to try a drug from a different family (see paragraph 61 of Professor Zimmlichman’s opinion).
The Applicant claimed that in the official guidelines to physicians there is no recommendation to combine ARB with CCB. Their witness claims that since ARB was newer, it was not sufficiently understood and there wasn’t enough knowledge to recommend combining it with other groups. Where it was recommended to combine ARB drugs with other ones from other groups this was not with CCB group drugs. Professor Dahlof relates to this, inter alia, in a paper where he is one of the authors: Willenheimer et al. “AT1-receptor blockers in Hypertension and Heart failure: clinical experience and future directions” (1999). On page 1004 the combination of ARB and ACE drugs is suggested. Waeber also suggests this combination (page 136S) and recommends developing Fixed Dose Combinations to treat hypertension.
It appears that Professor Dahlof’s explanation as to the lack of an explicit recommendation for such a combination is logical. From studying JNC VI it transpires that the ARB drugs were relatively new at that time (Page 2424 refers to them as ‘recently introduced’). They were recommended to patients that had poor tolerance of the ACE drugs. Later, for patients suffering Cardiac Failure and particularly those with angina, it was recommended to combine ACE with amlodipine and other drugs from the group. From here, Professor Zimmlichman concluded (paragraph 73 of his Counter-Opinion) that at least in certain cases the JNC VI citation recommends combining ARB and CCB type drugs. This conclusion by Professor Zimmlichman is convincing and is accepted by the Deputy Commissioner and it also sits well with the explanation provided by Professor Dahlof that this is a new family of drugs and so there was no blanket recommendation to prescribe them.
From the papers brought as evidence it appears that in parallel to the general recommendations for treating hypertension which did not include an unequivocal recommendation to combine ARB and CCB type drugs, there was research that focused on ARB as a new family, including the possibility of combining family members with other drugs. Some of the research focused on the newly approved valsartan.
Two research programs shown dealt with the combination of candesartan (from the ARB group) and amlodipine (appendices 10 and 11 of the Zimmlichman opinion). Appendix 10, Peter S. Sever “Clinical Profile of the novel angiotensin II type I blocker candesartan cilexetil” (1997)), deals with a material whose regulatory approval in Europe was still pending. The conclusion of the publication was that combining it with amlodipine is better than either drug taken alone. This conclusion is also reached in Appendix 11 (Farsang) which compares the efficacy of a combined treatment together with amlodipine, with treatment of each drug separately (amlodipine, cilexetil and a placebo in a control group). The conclusion is that the combination has a greater efficacy than either single material.
Another thorough research program that considered combined dosages started before the priority date and continued beyond it. This is the LIFE program (Appendix BD-49). A paper about the research program design was published back in 1997. This program included 9000 participants (see Professor Dahlof’s testimony, which notes that he was one of the researchers – protocol from 4 March 2015, page 50 onwards). This research looked at the effectiveness of losartan from the ARB group in treating a special population with hypertension. Doctors added different additional drugs to the treatment given to patients whose response was insufficient. If there was a need for an additional drug, 50% of physicians chose a CCB family member. The research terminated in 2002. Although this research essentially combined losartan, mestinon and a CCB member, including amlodipine which was the best seller in this group. This program supports the Opposers contention that there are logical combinations as Professor Zimmlichman explained, and also combinations that a reasonable doctor would not prescribe.
A paper that related at length to this is P. Prasad et al. “A Pharmacokinetic Interaction Between an Angiotensin II Receptor Blocker (Valsartan) and a Calcium Channel Blocker (Amlodipine)”, AJH – April 1997 – Vol. 10, No.4, Part 2) which describes research on healthy volunteers that took valsartan and amlodipine together (Appendix 12 of Professor Zimmlichman’s opinion).
“These drugs may be administered concomitantly in clinical practice and it is therefore important to examine the potential for a drug-drug interaction.”
A conclusion of the research was that the drugs could be taken together.
“Considering the variability and wide therapeutic range for VAL, it was concluded that there was no PK interaction between VAL and AML and these drugs can be safely administered together.”
Professor Dalhof related to this publication in his opinion and was cross-examined on it. He testified that research was conducted as part of the clinciial testing for obtaining regulatory approval for valsartan. Under cross-examination, Dalhof explained that in this testing, the blood pressure of healthy volunteers was not monitored. He thought that the test was to see the effect of one drug on the concentration of another, since a doctor is lilely to prescribe several drugs to a single patient. Professor Dalhof considers that this does not indicate that two drugs tested will necessarily be prescribed for lowering blood pressure. The Deputy Commissioner had difficulty accepting Professor Dalhof’s explanation since the beginning of the paper explains each drug was used for treating low or medium hypertension:
“These two drugs have different modes of action and can be administered with once a day regimen for mild to moderate hypertension.”
Further on, the paper noted that two drugs may be administered together (concomitantly) to patients, and so there is a need to test for interactions.
Since the test was done on healthy volunteers, the effect of the combination was lowering blood pressure was not tested. It is, however, difficult to conclude that the research was conduceted for theoretical applications where the drugs were given together for effects other than that indicated in the research, i.e. not for treating high blood pressure in patients suffering from hypertension.
One should note that the research of Prasad et al is the basis of the Physician’s Leaflet for Diovan referenced above and cited by Professor Zimmlichman who concluded from it that reasonable doctors would prescribe the two drugs concomitantly.
The Corea research on valsartan also compared between ints efficacy and usefulness against that of amlodipine. This research divided patients with low or medium hypertension into two groups. . Half received valsartan and the other half received amlodipine. Patients whose condition had not improved within eight weeks received additional amlodipine. From the publication it appears that 24 of the patients that received valsartan were then also given amlodipine.
Professor Zimmlichman was asked under cross-examination, regarding this research and a further research program that reviewed it (Anthony Markham and Karen L. Goa “Valsartan A Review of its Pharmacology and Therapeutic Use in Essential Hypertension” Drugs 1997 Aug: 54(2) 299 – 311 (appendix 16 to his Opinion). Professor Zimmlichman explained that the Corea research did not analyze the different results of those patients that received the combined treatment of valsartan together with amlodipine with those patients that received a single drug (monotherapy). However it is clear that amlodipine was given to patients treated with valsartan that did not react sufficiently out tf the thought that this will help, as Professor Dalhof admitted under cross-examination. From this it may not be concuded that the combination has an additive effect or that is better than another combination, however it is also clear that the researchers anticipated that the combination of the drugs would lower blood pressure more than Valsartan alone amongst those patients that did not respond sufficiently to the monotherapy.
Professor Dalhof related to all four medical programs that dealt with the combinations of ARB and CCB drugs. Professor Dalhof explained that he had related to the prior art and also to these research programs in his paper appended as BD20, and as a person of the art at that time, did not consider that it would be advantageous to combine these two families. In this paper it was theoretically suggested to combine ACE and ARB type drugs, however the conclusion was that ARB drugs are less effective than ACE but also showed fewer side effects. Under cross-examination, Professor Dalhof was asked how this conclusion sat with that stated in his Opinon that at the priority date it was the ARB group that was considered weak. The Deputy Commissioner concurs that the two statements do not sit well together, although Professor Dalhof explained that this was a widely held assumption back then, although he himself dissagreed.
The picture that arises from this is that at the priority date the ARB drugs were a new family for treating hypertension. Its activity is similar to that of the ACE but had fewer side effects. The general advice of the WHO was to combine drugs for treating hypertension, but there was no general instruction to use this family since there was not enough information to combine them and probably the high unit cost was also a factor in their not being actively recommended. From the testimony offered by both sides it is clear that physicians did prescribe ARB and CCB drugs together. There are also a number of papers that relate to combinations of drugs from these groups, including the specific claimed combination.
Professor Zimmlichman testified that in accordance with the activity of the families, there are ‘logical’ combinations of materials and also illogical ones (see paragraph 30 of his response).
Downside of Valsartan
One of the Applicant’s claims is that even if it were self-evident that to combine CCB materials and ARB materials, it was not at all self-evident to choose valsartan specifically, since it is less efficient than other ARB drugs.
This claim made by the Applicants was widely discussed in Professor Dalhof’s Opinion (sections 8.1.5 to 8.1.22) which dealt with the molecular structure of valsartan, it’s pharmacokinetic properties, the effect of taking it with food, and so on.
Professor Dalhof based himself on BD57 ׁ (George L. Barkis et al. “Clinical Efficacy and Safety Profiles of AT1 Receptor Antagonists” (1999), which published after the priority date. In this publication, the authors compare and contrast the pharmacokinetic properties of the group.
In his cross-examination, Professor Dalhof was asked about the fact that it was no longer controversial at the priority date to combine valsartan with HCTZ, a diuretic, as a known Fixed Dose Combination (FDC) sold as Co-Diavan. this does not sit with his deduction that people of the art would not have used valsartan in an FDC (see page 80 of the protocol from 4 March 2015). This combination was published in PCT/EP97/03172 which published on 31 December 1997. That publication sates that:
“The active agent valsartan is particularly suitable for combination with other active agents, e.g. HCTZ.
Further on, in the same publication, it is stated that the preferred dosage of valsartan is 80-160 mg, and 80 mg is demonstrated in the Application.
Professor Dalhof had reservations and stated that he does not make any claims regarding the effectiveness of valsartan but rather relates to its pharmacokinetics. With this, Professor Dalhof acknoweldged that he is not an expert in pharmacology and so it is difficult to accept his opinion in this regard. Furthermore, Professor Dalhof testified that after the priority date it was proven that valsartan was safe to use, very effective, and it became one of the better selling ARB type drugs. During cross-examination, Professor Dalhof was asked for data that showed that this success occurred only after the priority date but he did not provide support for this assertion (See page 81 of the protocol from 4 March 2015).
In response to the claim the opposers submitted the Opinion of Professor Golomb from the Department of Pharmacology. Professor Golomb related to these facts and explained that valsartan is in no way pharmacologically inferior to alosetron. The Deputy Commissioner did not ignore the fact that Professor Golomb has more or less continuously advised Unipharm for some 20 years and that several errors occurred in his Opinion which were orally corrected at the start of his oral testimony. Nevertheless, the Deputy Commissioner found that his evidence sat well with the publications exhibited. Furthermore, Professor Golomb stressed two important points: Firstly, that valsartan, like amlodipine is prescribed for taking once a day which makes it easier to take the two drugs concomitantly. Secondly, the relatively low biological availability of the material requires it needing to be taken in a higher dosage to attain the desired results, but this does not mean that the drug is ‘inferior’.
Regarding the relevance of the relatively low biological availability in drug development, Professor Golomb explained that once one knows the effective dosage, this is no longer significant. In this instance, the correct dosage of valsartan was certainly known as it was already marketed and the same dosage was eventually used in the Fixed Dosage Combination. Professor Golomb explained that low biological availability is only of importance in extreme instances, such as a lower biological availability than 10% which isn’t the case here.
During cross-examination Professor Golomb explained that the fact that valsartan is prescribed for taking once a day indicates an acceptable biological availability, rendering the Applicant’s arguments moot.
The Applicant’s claims regarding the disadvatages of valsartan do not sit well with their statements regarding the Co-Diovan Patent Application, where they presented the material as particularly suuitable for combining with other materials. It is known that the purpose of a Patent Application is to provide persons of the art with information that they can rely upon in developing other inventions in adjacent fields. Consequently it is fitting that the Applicant will stand behind statements made in a filed application, even if they are not helpful to him in this instance.
The Opposers turned to the case law that deals with the claim of ‘preconceptions’ concerning the combination. The Opposers noted that the Applicnats alleged such preconceptions regarding the ARB group as being ‘weak’ and CCB group as being ‘dangerous’. A British ruling on this issue: Cipla Limited and others v. Glaxo Group Limited  EWHC 477 (Pat) states that preconceptions, like general knowledge in the field, need to be common to the majority of practitioners and then it may be ascribed to the average person of the art.
The Applicant held that this claim is not that there is a preconception but that in light of prior art, it is not obvious to come up with the invention which teaches away from it.
Whether we consider such suspicions and beliefs as preconceptions or as general knowledge in the field, the Deputy Commissioner does not consider that the Applicants have proved that the view was so widespread as to direct researchers away from the invention. Professor Dalhof himself stated that he did not share these beliefs.
In summary of this point, the Deputy Commissioner does not hold that the Applicants have proven that the choice of valsartan was not self-evident.
Although considering it unnecessary to do so, the Deputy Commissioner points out that this choice is very logical and possible for the Applicant to reach this conclusion since they manufacture this drug, and so it is likely that they would direct their energies towards developing a fixed dose combination that includes at least one drug that they supply.
Inventive Step – Summary
This proceeding raises the question as to whether to deny inventive step, the Opposers have to show that persons of the art would reach the specific solution claimed or whether the solution is within a range of possibilities that persons of the art would consider is sufficient, even if they could have chosen an equally good alternative.
In this direction, the following stated by the English Court in HOSPIRA UK LIMITED v. GENENTECH, INC.  EWHC 3857 (Pat.) is pertinent to this ruling:
“Next, I must deal with the could/would debate. I have already explained why I do not accept that it is necessary in every case for the court to conclude that the skilled person acting only on the basis of the prior art and his common general knowledge would arrive without invention at the precise combination claimed. Given that the screening methods were part of the common general knowledge, that the tests involved were routine, that the excipients were common general knowledge excipients and that there was no a priori reason why a successful lyophilised formulation could not be made, it seems to me that it was beyond argument that the claimed combination in this case was one that could be made by the skilled team. The question is whether this is the type of case where it is necessary to go further and ask whether the skilled person would necessarily have made the precise combination claimed.“
In this context, it should be noted that the Applicant did not claim this combination was the best of all possible combinations. Such possible combinations that are capable of reducing blood pressure are taught in the prior art. The Applicant only claims that the combination is better than either drug taken alone. This was known to a large proportion of the clinical physicians in the field since treating hypertension with combinations of drugs selected from different families was common practice before the priority date as detailed above.
During the proceeding, the Applicant claimed that commercial success of Exforge indicates it being inventive. The evidence of it being commercially successful were sumbitted by Professor Dalhof who related to Novartis publications regarding Exforge sales in 2008. Professor Dalhof was cr0ss-examined about this and admitted that he had no personal knowledge regarding the sales and costs involved in developing the drug, and in advertising expenses incurred. Although commercial success is indicative of inventive step, one can only conclude this to be the case when considering all the contributory factors to the commercial success, which was not done in this instance, partly due to no competent witness being presented (see Terrell on the Law of Patents 14th ed. (1994) p. 131).
Due to the above, the Deputy Commissioner, Ms Jacqueline Bracha concludes that the invention does not include an inventive step and is, therefore, not patentable.
The Opposers raised issues that related to the lack of proof regarding the utility of the invention. The specification alleges a synergetic effect between valsartan and CCB family members, particularly amlodipine. The Application promises ‘a supra-additive effect’ with respect to the negative effects on the heart muscle. The Application describes tests on mice. One test involved mice with high blood pressure and another with mice suffering diabetes and hypertension. There is no doubt that the second test, which was allegedly to show the efficacy of the claimed combination, actually tested a different combination comprising valsartan and verapamil. moreover, the application itself does not show the particular efficacy of the combination,since it simply shows that this is one possible combination, and persons of the art would not neccessarily chose amlodipine out of the CCB family. As to the first test, it does not include comparative information that supports a synergetic or supra-additive effect.
Having ruled that there is no inventive stop there is no need to go into more detail. The parties agree that valsartan and amlodipine is good for hypertension and the combination is better than either ingredient taken by itself. This consensus is at the basis of the Opposers’ contention of lack of inventive step, but rather of a logical and possible choice. The prior art produced in evidence supports this contention.
Consequently, even if the Applicant did not show efficacy as promised in the specification, that does not mean that the invention is not useful. Neverthless, the Deputy Commissioner does think that the not demonstrated synergetic effect is neccessary to show inventiveness. What she means is that a selection of a best alternative from various options may indeed be patentable (See 8802/06 Smithkline Beecham vs. Unipharm), however in this instance there is no proven advantage of the selected drug over alternatives.
Teva requested costs of 1,149,814 Shequels and Unipharm requested costs of 1,576,794 Sheqels, both providing detailed calculations. The Applicant countered that the combining of the Oppositions was supposed to reduce the Opposers’ costs, and their working in parallel does not justify double expenses. The Applicant also alleged that the Opposers incurred additional expenses by non-optimal management of the case and by filing spurious arguments. Some evidence submitted was ruled as inadmissible, and there were some pointless requests relating to discovery. Furthermore the list of expenses submitted by Adv. Tal Band (Teva’s counsel) was laconic and included unnecessary expenses. Similarly, Unipharm’s reading of Teva’s statement of claims and work related to cancellation of evidence submitted by the Opposer, that was upheld as unneccessary, cannot be charged for.
In her ruling, the Deputy Commissioner Ms Bracha noted that both parties accepted that real costs were the basis of calculating awarded costs (see Appeal No. 891/05 Tnuva Cooperative for Marketing Israeli Produce Ltd. vs. The Ministry of Import and Export, Trade and Industry, 2005(2) from 30 June 2005.
She accepted however, that there was duplication and eventually ruled 49,670 Shequels for Professor Zimmlichman’s testimony, 25,000 Shequels for Professor Golomb, and a total of about 950,000 Shequels including VAT for the combined legal expenses.
Opposition by Teva and Unipharm to IL 140665 to Novartis, rulng by Ms Jacqueline Bracha, 29 September 2016
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