Teva Challenges Gilead Patent Application for HIV Treatment

drug cocktailThis ruling relates to a treatment for HIV consisting of a single once-a-day dosage that includes a combination of two or three different active ingredients.

Israel Patent Application No. 169243 to Gilead is titled “PHARMACEUTICAL COMPOSITIONS FOR COMBINATION ANTIVIRAL THERAPY”. It is the national phase of PCT/US2004/000832 filed on 13 January 2004 and claiming priority from a couple of US provisional applications filed on 14 January 2003. Gilead purchased Triangle so that they would have the capability of producing both  FTC and TDF and in a press release in Bioworld in 2002 which quoted Gilead’s Chairman and CEO, they announced their intention to develop a single dosage formulation that included TDF and FTC, referring to the chemicals by their trade names of Viread and Coviracil. This announcement preceded the priority date and since they announced that they did not anticipate difficulties in formulating the combination, their announcement undermined claims 1 and 12 directed to the combination of TDF and FTC in the standard dosages of Viread and Coviracil. There were additional independent claims for FTC and TDF together with an additional active ingredient – either Reyataz, Kaltera or Sustiva. However, that combination was used in a clinical trial for treating Hepatitis B that was also prior art. This ruling addresses and clarifies the requirements for prior art to be anticipating and what is required to provide an inventive step. It also relates to the issues of claim support, enablement and utility.

History

GileadIsrael Patent Application No. 169243 to Gilead is titled “PHARMACEUTICAL COMPOSITIONS FOR COMBINATION ANTIVIRAL THERAPY”. It is the national phase of PCT/US2004/000832 filed on 13 January 2004 and claiming priority from a couple of US provisional applications filed on 14 January 2003. On allowance the Application published for opposition purposes and Teva filed an opposition on 26 March 2009 and four months later submitted a detailed statement of case. On 1 February 2010, the Applicant requested permission to correct the application, and on 21 April 2010, Teva requested that the proposed amendments to the claims be refused. There was an intermediate ruling on this by the Commissioner on 22 June 2010, and on 27 June 2010 Teva withdrew their challenge to the amendments and the opposition continued with the amended claim-set. On 8 May 2011, the Opposer submitted an amended statement of case and Gilad submitted their response on 1 January 2012. On 23 September 2012, the Opposer’s evidence was submitted in the form of two affidavits, by Professor Richard Novak and by Professor Joseph Fortunak. On 24 July 2013, Gilad submitted their response in the form of Affidavits by Professor Robert Redfield and Professor G Stahly, and on 10 April 2014 further affidavits were submitted in response to points raised.

The witnesses were cross-examined over the period 8-11 June 2015, and the parties then submitted their summation statements. Gilead requested permission to submit a further response claiming that Teva had raised new issues which Teva opposed on principle, and on 24 July 2016, Gilad responded. These issues are related to within this main ruling on the case.

Teva’s Statement of Case

tevaThere are 32 claims of which seven are independent; 1, 12, 27, 28, 29, 30, 31.

The invention is a combination of anti-viral agents, specifically those that target the HIV virus.

Claims 1 and 12 are as follows:

  1. Use of a therapeutically effective amount of [2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid diisopropoxycarbonyloxy-methyl ester fumarate (tenofovir disoproxil fumarate) and (2R, 5S, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3oxathiolan-5-yl)-(1H)-py       rimidin-2-one (emtricitabine) and one or more pharmaceutically acceptable carriers or excipients in the manufacture of a co-formulated composition for the treatment of a patient in need of an anti-HIV therapy, wherein said tenofovir disoproxil fumarate and emtricitabine are present in  said co-formulation in an amount of 300 mg and 200 mg, respectively, and said co-formulated composition is in the form of a tablet.
  2. A pharmaceutical co-formulation comprising [2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid diisopropoxycarbonyloxy-methyl ester fumarate (tenofovir disoproxil fumarate) and (2R, 5S, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine) and one or more pharmaceutically acceptable carriers or excipients, for use in the treatment of a patient in need of an anti-HIV therapy, wherein said tenofovir disoproxil fumarate and emtricitabine are present in said co-formulation in an amount of 300 mg and 200 mg, respectively, and said co-formulated composition is in the form of a tablet.

Claims 27, 28 and 29 are for dosages of FTC and TDF together with one of Reyataz, Kaltera and Sustiva. Claim 30 is for 300 mg TDF, 200 mg FTC and Sustiva together with common pharmaceutical additions. Claim 31 is for a kit including at least one co-formulation including both FTC and TDF.

Claim Construction

claim constructionThe Commissioner construed various terms used in the claims in accordance with the specification and the expert opinion and then considered whether any of the claims lacked novelty and/or inventive step.

Chemical Stability was understood in accordance with page 5 lines 11-19 of the specification as meaning the stability of combinations of two main anti-viral compounds against chemical disintegration and refers to shelf-life of the combination and also means that one compound does not adversely affect the efficacy of the other.

Synergy is defined on page 5 lines 26-28 as indicating that the effect of the combination of two active ingredients is larger than the sum of their separate effects and the active ingredients may be co-dispensed or dispensed in turn in separate formulations.

Enantiomers are chiral molecules that are mirror images of one another. Furthermore, the molecules are non-superimposable on one another.

TDF is [2-(6-amino-purin-9-yl)-1-methyl- ethoxymethyl]-phosphonic acid diisopropoxycarbonyloxy-methyl ester fumarate, and is short for Tenovir disoproxil fumarate. It is the prodrug of Tenofovir and it delays the activity of the reverse transcriptase of the HIV-1 virus (NRTI type), thereby preventing the building of the DNA sequence of the virus. In 2001, TDF received FDA approval in the US as a component of the commercial formulation Viread.

FTC is (2R, 5S cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one known as emtricitabine. It is the enantiomer of FTC and inhibits the NRTI enzyme. Emtricitabine was approved for treating HIV under the trade name Emtriva. 3TC is a derived analogous RTI inhibitor that is marketed together with AZT.

Reyataz, Kaltera and Sustiva are trade names for atazanivir sulfate, lopinavir/ritonavir and efavirenz.

Other terms defined were Retrovirus, Reverse transcription, HIV, HIV-1, NRTI/NtRTI, Mutants and Prodrug.

The Applicant alleged that the claimed combinations are advantageous in that they are chemically stable and act synergistically. The combination is alleged to dampen the side effects of one of the ingredients. The combination of these drugs in one tablet sold as TRUVADA revolutionized the treatment of AIDS as it reduced the frequency of resistant mutant strains of HIV and was subsequently found to prevent healthy people contracting AIDS.

In the Background of the Application, low dosages were explained as reducing the frequency of the occurrence of drug resistant mutations. The idea of combining different active ingredients was widely discussed and it was noted that it was easier for patients to comply with lower dosage regimes. The Background also explained that RT and Prt enzyme combinations were widely used and effective, but that their efficacy was limited due to their being poisonous and because of the development of resistant mutant strains. Nevertheless, RT and Prt combinations were known to have synergetic effect in repressing the reproduction of the HIV virus.

It was noted that alongside the advantages of combinations, in 30-50% of patients combinations were ineffective. Sometimes patients develop a resistance to the drug, and in other cases they are unable to stick with complicated treatment regimes. Furthermore, there was the problem of poisoning. These problems justified the need to develop a new treatment to inhibit HIV-1 that overcomes these deficiencies, particularly dosages, with a preference of once a day with less side effects. The treatment is required to overcome mutations of HIV with distinct resistance profiles.

The use of combination of compounds can yield equivalent antiviral effect with reduced toxicity, or an increase in drug efficacy.

The specification (page 2 lines 29-30) notes that chemical stability is important. On page 17 it is explained that one must pay attention to the chemical stability of active ingredients to minimize impurities, thereby increasing shelf-life.

The Opposer alleged that the Application lacks utility, novelty and inventive step as required by Sections 3, 4 and 5 of the Israel Patent Law 1967, and further alleged that the specification was not sufficiently detailed and was not enabling contrary to Sections 12 and 13. There was also a 7(i) objection that the invention related to a method of treatment, but this was not developed.

In summary, the Opposer claims that combinations of compounds that inhibit enzymes was known prior to the priority date, and these included the specific combination of FTC and TDF for treating HIV.

Novelty

bioworldThe main allegations of lack of novelty were raised against claims 1 and 12 which were considered as separately anticipated by two different publications. In Bioworld Today, Vol 13, No. 233 page 1 there was a paper titled ” Gilead, Triangle Plan Merger: $46M Deal Pairs HIV Drugs”. The second publication was Ristig et al. The Journal of Infection Diseases (2002) pp. 1844-1847.

The Bioworld publication was a press release by the Deputy Head of R&D of Gilead to the effect that they intended to develop a combination of FTC and TDF and that this was not expected to have serious complications. The combination was expected to be particularly suitable due to the lack of mutations that are resistant to both active ingredients and its development was expected to be straightforward.

foot and mouthThe Opposer notes that in Bioworld, the Chairman and CEO are also quoted as announcing that they were intending to develop a formulation that included TDF and FTC, referring to the chemicals by their trade names of Viread and Coviracil. They mentioned that it would be a co-formulation and that it would be dispensed in once a day doses. The Opposer alleged that Gilead’s referring to the trade names effectively anticipated the dosages of 300 mg and 200 mg respectively as these are the dosages of Viread and Coviracil.

Teva alleges that not only TDF and FTC but also the third optional ingredient were all well established prior to the priority date, as was the combination of enzyme inhibitors in the treatment of HIV.

The Ristig publication also mentions the combination of FTC and TDF on page 1845, right hand column, paragraph 3.

The Bioworld publication was essentially a press-release in a publication that refers to itself as Biotech’s Most Respected News Source for Over 12 Years. The press release related to Gilead’s purchase of Triangle and to the anticipated development of an HIV treatment based on FTC.

The Biworld publication cited John Martin, President and CEO of Gilead:

“The drugs have no overlapping resistance mutations, he noted, which suggests “they would be highly compatible when used in combination. This could result in the first combination product dosed as one pill, once daily.”

The VCO R&D was quoted as stating:

“…the co-formulation work is “currently ongoing, but based on the physical chemical properties of both components, we don’t anticipate there will be any big challenges in doing that. The regulatory pathway, he added, is “pretty clear. All we would really need is a CMC [chemistry, manufacturing and controls] package, plus a bioequivalence study to show the co-formulated tablet gives you the same exposure to the individual components. The work involved is not that much. A bioequivalence study takes four weeks or so. Studies already are under way testing Coviracil in combination with Viread for HIV…”.

Gilead claims that the Bioworld publication is merely a press-release that does not include any technical information and is not sufficiently detailed to enable preparation of the claimed invention and to reduce it to practice. They added that the publication was not in a scientific journal, but rather in a ‘financial tabloid’. The publication includes financial rather than scientific information and backed this assertion by the expert witnesses admitting under cross-examination that they had not previously been aware of the publication.

Gilead focused on the fact that persons of the art would not learn from the Bioworld publication that the co-formulation was expected to be difficult due to problems of chemical stability and mutation resistance. They consider that the publication has to be read in its context to understand how it would be read and understood by persons working in the field. Since the publication was financial it would not be read by persons of the art anyway, and it simply related to Gilead’s purchase of Triangle and was merely hearsay by the author.

Gilead challenged Teva’s assertion that the article’s referring to the trade names Coviracil and Viread was insufficient to conclude anything regarding dosages in a co-formulation.

As to mutations common to both drugs, Teva alleged that the Bioworld publication shows that there is no problem with this. Relying on expert witnesses, Gilead argued that persons of the art would not change their minds because of that published in a financial publication.

Gilead considers that the details of the claims are not explicit in the Bioworld publication and the onus is on Teva to substantiate their allegation that these details are inherent.

Section 4 of the Israel Patent Law 1967 defines that Novelty is a lack of publicity regarding the invention, whether in Israel or abroad, whether by published description or by demonstration, prior to the date of reference:

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 cancel the novelty of an invention, the prior art publication should describe the elements of the invention in a way that enables average persons of the art to implement the invention as claimed (See Appeal 345/87 Hughes Aircraft vs. State of Israel, p.d. (4) 45:

The first rule is that to prove novelty destroying prior publication one has to identify a single document that describes the invention in its entirely and it is not sufficient to create a mosaic of different documents to create a general picture. A general description is insufficient to remove novelty if it is not enabling and does not provide enough signposts leading to the invention of the patent.

The novelty test must relate to the substance disclosed and not to the form and wording. So it is not enough to rely on common words or terminology in the patent claim and the prior art. When examining a piece of prior art it is permissible to arm oneself with the general professional knowledge at the time in question, but this cannot be used to read in principles or elements that are not mentioned in the prior art. See also IL 138831 Elbit Systems vs. Rafael Advanced Military Systems from 30 June 2013. 

Similarly, in Appeal 4867/92 Sanitovsky vs. Tams ltd et al, p.d. 50(2), 509:

The essence of the invention is that part that is central and essential to the workings of the invention in contradistinction to elements that can be substituted for or left out entirely. the main core will remain protected even if an essential element is switched for another that performs the identical function. 

This is the so-called doctrine of equivalents developed in the US in Graver Mfg. Co. V. Linde[11] (1950) about which Shamgar wrote in Appeal 345/87 that

 switching a component will not prevent a finding of infringement if the competing product functions in essentially the same way as does those claimed.

If so it is appropriate to consider whether persons of the art would be exposed to the Bioworld publication and if that disclosed therein is sufficient to anticipate the claimed invention. Citing Terell 17th edition pages 11-28, the Commissioner considered it appropriate to consider who the target audience of the citation was.

The Commissioner rejects Gilead’s experts finding that persons of the art would not give weight to that published in a journal such as Bioworld, and would probably not even see it. This is unacceptable in the information age where publications are freely searched.

The publication is not a scientific paper and it appears to be directed at investors. It does not provide an enabling disclosure, so the Commissioner is willing to consider its relevance with other publications as to whether or not there is an inventive step.

In this regard one can draw a parallel from similar principles regarding whether prior art knowledge that includes the name of a chemical compound is novelty destroying. The US case-law establishes that naming a chemical or even its formula is only novelty destroying if its method of formulation is known, either to persons of the art, or in a separate publication. See  Chisum on Patents, Vol. 1 2015, §3.04[1][c]-3-150:

“Chemical compounds present special problems in determining whether a description is adequate to constitute anticipation. Mere identification of a compound by name or formula may represent mere speculation, particularly where it is part of a lengthy listing of compounds.

A reference naming a compound must first meet the enablement requirement. A method of making the compound must either be obvious to one with ordinary skill in the art or to be disclosed by the reference…

…Even where the method of making is well-known, an apparent naming of a compound by formula may not constitute an anticipation…

…In re Wiggins (1970), the court held that the speculative listing of a theoretical compound will not necessarily anticipate even where the prior art discloses means of preparing that compound…”.

A similar finding is given in Terrell in 11-02:

“…A disclosure of e.g. the existence of a chemical substance is not enabling (and therefore not an anticipation) if the skilled reader would not know from the information given how to produce or obtain it, or how to obtain or to make the required starting materials. Merely being told that it exists is not itself enough”.

The principle regarding whether a piece of prior art is anticipatory is whether the publication discloses the claimed invention, its details and whether it would require additional stages or tests to reduce to practice. The commissioner concludes that despite the Bioworld publication mentioning names of medical formulations that the Applicant tried to combine, this does not teach anything with certainty regarding dosages to be included in the final tablet.

The nature of a multi-element invention such as that claimed will not necessarily be explained in a business or financial publication. Once cannot, however, dismiss financial publications from being anticipatory. The guidelines for US Examiners MPEP 901.06 states that: All printed publications may be used as references, the date to be cited being the publication date. See also Terrell 11-06. But these publications do need to be enabling disclosures to the extent that the desired product is the only solution. Since the Bioworld publication lacks certain details that are claimed, the Commissioner does not find it anticipates claims 1 and 12.

Ristig

The Ristig publication describes a limited clinical trial designed to test a treatment for hepatitis. Teva notes that one of the patients was given TDF and FTC together which was proof of concept that these could be safely combined to treat HIV.

The Applicant alleges that the publication is not relevant and if anything, teaches away from the invention. The research considers co-formulations of tenofovir and FTC against Hepatitis B virus and not against HIV. The publication notes that three of the patients were HIV carriers as well and were having treatment for HIV that was not mentioned.

The Ristig publication is close to the invention but is missing critical ingredients that are essential when treating HIV. Whilst it does teach a co-formulation to get effective results, it is indefinite.

… so they are taking a bunch of HIV drugs that included  either 3TC or FTC, and they added Tenofovir to the regimen, and they saw an anti viral effect and so while this is not a definitive trial, it is a proof of concept that you can actually combine both Tenofovir and FTC in the same patient and get a positive effect…

So the commissioner concedes that neither Bioworld nor Ristig teach the invention to persons of the art. However HIV and HBV have similarities as the President and CEO of Gilad state in Bioworld:

Martin noted a Phase III trial also is ongoing with Coviracil in chronic hepatitis B, HBV, and “the treatment paradigm for HBV may mirror that of HIV, making feasible a co-formulation with Hepsera”.

Inventive Step

Section 5 defines inventive Step (Non-Obviousness) as follows:

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 stated in section 4.

In Hughes Aircraft it is established that to destroy inventiveness it is legitimate to cobble together a number of publications to create a general picture when considering whether or not there is an inventive step:

The basic question of inventive step is determined by considering the total professional knowledge in the relevant field, and to do so it is legitimate to join different publications into a general picture Appeal 3314/77 [1] page 209. However, one must always bear in mind that the joining together of the disparate documents must be obvious to persons of the art at the date in question; for if it requires an inventiveness to do so, particularly where scattered crumbs of knowledge are gathered together – the general picture obtained is not obvious and one cannot say that the patent has no inventive step.” –page 111.

See also Sanitovsky pages 515-516 and Appeal 793/86 Michael Porat vs. Tzamal Modern Medical Equipment, p.d. 44(4) 578, 585.

From the above discussion it is clear that the combination of FTC and TDF was discussed in Ristig with respect to the treatment of Hepatitis B. Additionally, in the Bioworld publication the Applicant’s senior management did not themsleves foresee significant difficulties in using this to treat HIV and they themselves drew a parallel between HIV and HBV. Where the dosage is not considered surprising by any of the expert witnesses of either side, it would appear that the combination of the two references teaches that claimed in claims 1 and 12.

The Commissioner rejects the Applicant’s claim that resistance to mutations is indicative of an inventive step. It is accepted that development of mutant drug resistant strains of HIV is one of the problems with developing drugs in this field. These mutations are due to changes in the DNA of the virus. Since the virus does not have a good quality control, it does not replicate exactly. This makes treatment difficult since after mutating, the response to treatment can change.

TEVA related specifically to the mutation that resulted in treatment by FTC and TDF in combination. Relying on that known at the time, Treatment by Tenifor and TDF were expected to result in the K65R mutation which had cross-resistance to FTC. This mutant variant resulted in a synergic lowering of HIV sensitivity to FTC. However, TEVA considered that it was known that one could raise the genetic barrier of tenofovir to prevent the K65R mutation from forming y combining TDF with zidovudine which is also known as AZT.

GILAD responded that the result of published clinical trials indicated combining tenefovir or TDF with 3TC and NOT with zidovudine, i.e. that the combined treatment of two materials was expected to allow the fast development of a resistance to the combination and to the treatment having disastrous results. GILAD noted that at the relevant date only the combination of terofovir with zidovudine was known to have a high synergistic effect. However, TEVA produced a large number of publications including Wainberg, Fridland and Fung that showed that combining TDF with 3TC (explained on page 15 lines 7-10, 15-17 of the application as being analogous to FTC) was known and considered as possible, despite the likelihood of mutation development. From here, persons of the art seeing the prior art publications would consider that claimed in claims 1 and 12 as obvious. Similarly, claims 2-6, 9-11, 12-21 that relate to the combination of TDF and FTC do not add anything that is not self-evident to persons of the art and the Applicant does not argue differently.

Additionally, claim 31 claims a kit that includes at least TDF and FTC and instructions for use. Although this is not written as a dependent claim, it does not have inventive step since the claimed ingredients are those of claims 1 and 12, and the inclusion of instructions for use cannot in and of itself be considered an inventive step.

The only question remaining is whether the addition of a third active ingredient such as Reyataz, Kaltera or Sustiva which are claimed in claims 7, 8, 22-26, 27, 28 and 30, can be considered inventive.

Claim 7 addresses the combination of TDF and FTC as claimed in claim 1, together r with an additional active ingredient that can be PI, NRTI, NNRTI or an inhibitor:

7. The use according to claim 1, wherein the co-formulated composition further comprises a third active ingredient selected from an HIV protease inhibitor (PI), an HIV nucleoside reverse transcriptase inhibitor (NRTI), am HIV non nucleoside reverse transcriptase inhibitor (NNRTI), and an HIV integrase inhibitor. 

Claim 22 depends on claim 12 and adds a third antiviral agent:

22. The pharmaceutical co-formulation of any of claims 12 or 21, further comprising a third antiviral agent.”

Claim 23 depends on claim 22 and recites that the third antiviral agent can be PI, NRTI, NNRTI or an inhibitor and so is similar to claim 7. Claim 24 specifies PI and claim 25 specifies NNRTI.

Although claims 7, 22, 23, 24 and 25 do not identify the third active ingredient beyond its anti-viral effect, claims 8. 26, 27, 28, 29 and 30 specify Reyataz, Kaltera or Sustiva.

TEVA  claims that before the priority date, persons of the art knew about treatments combining known anti viral agents that resisted HIV. In light of this, persons of the art would be motivated to develop formulations of the type described and would have a reasonable expectation to succeed. The Applicant attempted to argue chemical stability issues as if this was a problem they tried to solve. The Opposer challenges this attempt by referring to the Bioworld publication which states that the development was not expected to be challenging.

The Applicant does not dispute that at the relevant date there were attempts to combine treatments for HIV, but does not consider this as anticipating the invention or rendering it obvious. These attempts do not make the combination obvious since obviousness would require a reasonable likelihood of success and not merely a hope of success.

The experts concur that persons of the art would know that single active ingredients would not work and that one has to prescribe a combination of drugs. However, the appropriate combination would not necessarily be known.

As the Applicant notes, at the priority date, there were combinatory treatments that included three NRTIs or a PI and a NRTI or two NRTIs and an NNRTI. There were a wide range of known antiviral agents that could be combined in various permutations. The problem is to make effective combinations that have long-term effectiveness against mutations. Teva’s witness concurred that there were a large number of combinations that were unsuccessful. Gilead admitted that there had been a large number of tests with different combinations, including combinations expected to fail. Gilead considered that “scientists declaring an intention to do some trial does not mean that persons of the art considered that the trial was logical or likely to succeed.

In the ruling concerning Teva’s Opposition to IL 136294 to Pharmacia & Upjohn AB, 30 September 2014,  it was ruled that the issue of likelihood of success as indicative of inventive step would be considered in light of the circumstances:

Determining that an invention lacks inventive step does not require that the path chosen by the Applicant will necessarily lead to the invention. Some likelihood of success is sufficient, and the amount required depends on circumstances.

The circumstances depend on the field and the expectations of practitioners where a reasonable expectation is a basis for expecting success and not merely hope by the experimenter. Gilead referred to Medimmune Ltd v Novartis Pharmaceuticals UK Ltd ,[2012] EWCA Civ 1234:

“One of the matters which it may be appropriate to take into account is whether it was obvious to try a particular route to an improved product or process. There may be no certainty of success but the skilled person might nevertheless assess the prospects of success as being sufficient to render an invention obvious. On the other hand, there are areas of technology such as pharmaceuticals and biotechnology which are heavily dependent on research, and where workers are faced with many possible avenues to explore but have little idea if any one of them will prove fruitful. Nevertheless they do not pursue them in the hope that they will find new and useful products. They plainly would not carry out this work if the prospects of success were so low as not to make them worthwhile. But denial of patent protection in all such cases would act as a significant deterrent to research.”

In light of the many attempts that the Applicant referred to and the Opposer did not challenge, one can accept Applicant’s assertion that one cannot assume a priori what the result of combining TDF, FTC and a third ingredient would be. This is mainly due to the risk of rapid creation of mutations and possible effects of one chemical on the other. This could lead to a conclusion that the three-way combinations with specific dosages are not obvious to persons of the art. Further evidence of this can be found in the commercial success of ATRIPLA which includes efavirenz as the third active ingredient. It appears, therefore, that claims 8, 26 and 30 do have an inventive step.

Support for claims in the Specification

The specification focuses on two active ingredients taken together – TDF and FTC. The Opposer’s claims regarding the scope of the claims and the sufficiency of the specification focuses on the third ingredient.

As stated previously, the Applicant acknowledges that reaching a successful combination requires a large amount of experimentation. The application and the evidence related to the motivation and efficacy behind the basis of combining FTC and TDF. As to the third ingredient, the only thing stated in the specification is that this does not adversely affect the synergy of the two main ingredients, and the third ingredient may be any of a long list of ingredients given in table A of the application on pages 27-29 thereof. Furthermore, the author of the patent application considers this an open list (see page 26 line 5). Thus the applicant does not claim a three-way synergy.

The Application provides a wide range of possible third ingredients but does not claim any advantage of one or another. The Applicant also has stated on record that persons of the art would try various combinations. The Application does not specify the advantages of specific combinations and dosages, which persons of the art might try.

The Applicant’s expert witnesses related to various difficulties with certain combinations, such as granularity which continued to be an issue after the priority date and that certain combinations were toxic. However, the Application itself does not include an explanation regarding which combinations were solutions to these problems.

As explained in the Background of the Application, the HIV-1 virus includes three enzymes that are required for replication: integrase, protease and reverse transcriptase. Before the priority date it was typical to use formulations that attached the first two, particularly in combination. However, their efficacy was limited by their toxicity and by the development of resistant strains – see page 1 line 30 of the Application. In the specification it is stated that use was made of many systems of combined treatment to test the effect of the drug-drug interactions. However, the application does not relate to how the third ingredient addresses these issues. Since the Applicant itself raises this issue in the Application, they should have provided explanations to persons of the art regarding which combinations overcame these issues and in what manner.

They were particularly obliged to relate to this for specifically claimed third elements. In this regard, Reyataz, Kaltera and Sustiva as claimed in claims 7, 27, 28, 29 and 30 are known ingredients of drug cocktails and their dosages are known.

Furthermore, in claims 27-28 which do not detail dosages of TDF and FTC and are thus wider than claims 1-12, there is a greater likelihood of poisoning, and the effect of a third agent is not discussed.

Section 13(a) of the Law states that:

The specifications shall end with a claim or claims that define the invention, on condition that each said claim reasonably arise out of the subject described in the specification.

Thus the claims define the extent of the protection provided by the patent. The explanation of the claims should be done with respect to the specification in its entirety, including the figures and text (see Hughes, 65).

In Appeal 8802/06 Unipharm Ltd. vs. Smithkline Beecham PLC, 18 May 2011 it is stated that:

In accordance with Section 13 of the Patent Law, the protection of the invention is determined by the claims that define the invention, and not be the specification as understood in Section 12, which includes the title and description (see Hughes p. 68); however one can refer to the specification to explain the nature claims  (see Appeal 2972/95 Yosef Wolf and Partners, ltd. vs Beeri Press Limited Partnership, p.d. 53 (3) 472, 477 (1999).

See also Appeal 8706-11-12 David Becher vs. HaMivreshet Tuchama Agricultural Cooperative Ltd 8 August 2014 (there was an Appeal regarding costs of this that was submitted to the Supreme Court which was refused).

In this instance, there is no doubt that what is claimed appears in the specification in one way or another. Whilst the combination of the third active ingredient is not shown in Examples, it is related to in the Specification. However, the discussion is insufficient to support the claims. Combinations are claimed without dosages yet the Applicant himself raises issues of toxicity and the development of resistant strains. Claims 7, 22, 23, 25, 27 and 29 do not provide dosages of TDC, FTC or the third ingredient and the specification does not provide this information. It can be concluded therefore, that the three-way combinations are not properly supported. Similarly claim 31 is wider than the specification and is not properly supported.

Section 12a of the Law states that the specification should be enabled to the extent that persons of the art can implement without undue experimentation:

The specification shall include a title by which the invention can be identified, its description with drawings that may be necessary, and also a description of the manner in which the invention can be performed, enabling a skilled person to perform it.

The issue of adequate disclosure is related to in the decision concerning Teva’s opposition to IL 142809 to Pharmacia AB 26 February 2015:

…This requirement is a result of the deal at the basis of patent law under which in return for the monopoly on the invention, the public receives the knowledge inherent in the invention at the end of the protection period. (see Appeal 217/86 Mordechai Schechter vs. Abmatz Ltd. 44(2) 846, 852. From here, it is required that the specification must enable persons of the art to implement the whole scope that is claimed. A specification that conceals information that relates to part of that claimed sins against the deal and its purpose, as the Supreme Court ruled in Sanofi, page 744:

The Application has to include the promise of effectiveness of the formulation and sufficient details to enable persons of the art to fabricate. These requirements are a quid pro quo for receiving the patent for the invention.

 The amount of detail requires for Section 12 is a question of fact which depends on the field and its complexity:

The sufficiency of a specification is a question of fact and necessarily depends upon the nature of the invention and attributes of the skilled person.” ( Hollister [1993] R.P.C. 7 para. 10-14). 

In this instance, the specification lacks information and explanation regarding the addition of the third ingredient. It merely includes a laundry list of possible third active ingredients that may be combined. It does not enable persons of the art to known how the third ingredient should be combined to achieve an effective formulation. Thus claims 7, 22, 23-25 and 27-29 are not sufficiently supported.

Additional Claims

The Opposer claims that the invention lacks utility at the time of filing due to differences between the priority document and the allowed application.

The way to consider utility is explained in Appeal 665/84 Sanofi ltd. vs. Unipharm ltd. 41(4) 729, 10 December 1987 which states that:

The standard measure of utility is whether persons of the art doubt that promised in the specification, and if so, whether the Applicant has submitted experimental or other evidence that is persuasive regarding the alleged utility. The Patent Office Policy regarding therapeutic inventions is given in the guidelines updated in 1997…

The Application does not include any examples of the effect of the third ingredient. Thus claims 7, 22, 23, 25 and 27-29 which describe the addition of a third active ingredient without dosages, lack a convincing case of their having utility.

As to the priority claim, Section 10(a)(4) of the Law regards the support required by  the specification and that required by the priority document as having the same standard. There does not need to be literal support but substantive support is required. The Applicant can add improvements and additions, but these do not widen the protection from that of the priority document. As stated in 520/80 Rosenberg vs. Rubinstein, p.d. 38(1) 85:

There is no requirement for literal support but only for substantive support and the Applicant may include additions and improvements that were developed after the filing of the priority application, so long as they do not widen the field of the monopoly.

See also Opposition to IL 138829 Teva Pharmaceutical Industries vs. Eli Lilly and Co. 28 February 2017.

The Opposer alleges that the priority document does not relate to the issue of chemical stability that is claimed in the Application itself. Examination of the priority document reveals that it does relate to “cross-resistance” and to resistance to mutations and the problem of combining active ingredients. The Application does not add new subject matter and the Opposer’s allegation is rejected.

As an afterword, the Opposer’s response does not exceed that discussed previously and so there is no need to allow the Applicant the last word.

Conclusion

Claims 1-7, 9-25, 27-29, 31 and 32 lack inventive step. Claims 7, 22-25, 27-29 lack enablement and claim support. However, claims 8, 26 and 30 are allowable.

Thus the Opposition is partly allowed and if Gilead submits a new claims set based on claims 8, 26 and 30 within 30 days, it will be allowed. Otherwise, the file will be closed. Applicants may request costs as per Circular M.N. 80.

Opposition by TEVA to IL 169243 to Gilead, Ruling Asa Kling, 9 April 2017

COMMENT

Over Israel Independence Day there were various TV documentaries covering various events in Israel’s history and in two separate documentaries, Shimon Peres created untold damage by opening his mouth. In the first case he came back from Amman with a peace offer from King Hussein and mentioned that the day was of historic importance before reporting back to Rabin. Hussein was furious. In the second case, he told the world about Operation Solomon, the airlift of Ethiopian Jews to Israel, and thereby effectively brought the mass exodus to an end. It is not just politicians who like to talk. Gilead’s deputy head of R&D more or less undermined their attempt to patent this combination by his announcement in Bioworld today. Papers by inventors are surprisingly often the closest prior art and often anticipate inventions.

In the present instance, the Commissioner seems to require extraordinarily high standards for publications to be considered anticipatory and novelty destroying. This apparently contrasts previous rulings where the standard required was that of being ‘obvious to try’.

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