Amending the Specification of an Opposed Patent Application

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Under Israel Law, allowed patent applications publish for opposition purposes for three months prior to issuing. If an opposition is filed, the issuance may be delayed for rather longer, if the patent issues at all.

As a general rule, the Applicant may amend ‘scribal errors’ i.e., typos in the specification and may narrow the scope of coverage of the claims, but cannot add material or widen the claims to cover something not previously within their ambit. In practice, applicants often request amendments that are allegedly permissible but which the opposer considers as somehow adding material or widening the monopoly sought. Sometimes amendments are opposed as a delaying tactic as until a patent issues, it cannot be enforced.

In the present instance, the application in question is IL 122546 to Abbvie Inc. titled “COMBINATION OF RITONAVIR AND A DRUG METABOLIZED BY CYTOCHROME P450 MONOXYGENASE AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME”, which was filed two decades ago on 28 June 1996 by Abbot Laboratories as the national phase of PCT/US1996/0011015 which itself claims priority from a US provisional application (no 60/000654) filed on 29 June 1995. The case was transferred to Abbvie in June 2013.

The case was allowed and published for opposition purposes on 31 January 2012, and on 29 April 2012 oppositions were filed by Vertex Pharmaceuticals and by Teva Pharmaceutical Industries LTD.

Abbvie petitioned to amend the claims and this interim ruling relates to the proposed amendment and examines whether it is supported and whether it is indeed a narrowing of the scope of the claims.

last minuteIn his ruling of 2 May 2016, the Commissioner Asa Kling allowed the amendments to the claims but this is an interim ruling anyway and the patent, if eventually granted, will lapse anyway 20 years from filing on 29th June 2016. This begs the question as to the point of continuing with the opposition?!

The ruling has been carefully translated and is reproduced below but I have added a break as it may not be of interest to everyone…

On 12 November 2012 the Opposers submitted their statement of cases, but prior to filing their counter-claims, on 2 January 2013, Abbvie submitted a request to amend the claims. On 3 March 2013, both Opposers opposed this amendment, for different reasons. Neither opposition was backed up with evidence, since both opposed on procedural grounds. On 2 July 2013, the Applicant responded, and appended an expert testimony from Professor Abraham Danon. On 2 October 2013, Teva announced that they were not bothering to respond, but on 18 November 2013, Vertex responded and submitted an expert opinion by Professor Joseph Krako.

As per guidelines in an old Commissioner Circular (M.G. 35) titled “Correcting a Patent Specification During an Opposition Proceedings”, that was in force at that time, the Opposition itself was frozen pending a decision on the amendment.

On 28 January 2014, a request b y the Applicant to delete evidence submitted in a response by Vertex was refused. In accordance with an interim decision by the Commissioner,that issued on 31 December 2013, a hearing involving all the parties was held on 11 March 2014, during which both experts were cross-examined on  their opinions and then the parties submitted their summaries. Abbvie requested that Teva’s response to the summation be struck from the record as they claimed it was more than a response to a summation and was rather a summary whose length exceeded anything submissible as a response to a summation, or that Abbvie should be entitled to respond themselves.

Before addressing the claim amendments, the commissioner decided to allow the response to submission to remain of record on the basis of his determining that the issues discussed were those previously raised and that the response was indeed a response to a summation.  Likewise he saw no reason to allow the Applicant to have the last word. The Commissioner ruled that the proper way to address the lengthiness of the summation was in a costs ruling.

Substantively, and quoting from the specification:

“The present invention relates to the use of a combination of a drug or a pharmaceutically acceptable salt thereof which is metabolized by cytochrome P450 monooxygenase and ritonavir or a pharmaceutically  acceptable salt thereof for improving the pharmacokinetics of said drug in the preparation of a medicament; wherein the drugs MK-639, SC-52151 and KNI-272 are excluded”.

The purpose of the invention is to delay retroviral proteases, particularly the HIV protease.

The Application as allowed (version 2) had 62 claims, three of which, claims 1, 33 and 46 were independent.

The requested amendment was to add a specific 3A4 Enzyme to some of the claims. The Applicant claimed that the 3A4 enzyme is a specific Isl-enzyme selected from the P450 cytochrome monooxygenase enzymes that are claimed in claim 1:

“The use of a combination of a drug or a pharmaceutically acceptable salt thereof which is metabolized by cytochrome P450 monooxygenase 3A4 and ritonavir or a pharmaceutically acceptable salt thereof for improving the pharmacokinetics of said drug in the preparation of a medicament; wherein the drugs MK-639, SC-52151 and KNI-272 are excluded”.

The Applicant alleged support from the amendment from page 2 of the specification. Similar amendments to claims 2,3,11,18,19, 27, 35, 36, 49 and 54 were requested, and some of the drugs listed were deleted. According to the Applicant, the list of drugs that is metabolized by the 3A4 iso-enzyme is reduced to a number of  specific drugs and so the claimed invention is narrower. Likewise, Applicant requested that claims 4, 12, 20, 28, 37 ,50 and 55 and their dependent claims be canceled.

Finally, an amendment to claim 46 was requested to including the underlined words in claim 46 recited below:

“The use of a combination of a drug or a pharmaceutically acceptable salt thereof which is metabolized by cytochrome P450 monooxygenase 3A4 and ritonavir or a pharmaceutically acceptable salt thereof for improving the pharmacokinetics of said drug in the preparation of a medicament; wherein the drugs MK-639, SC-52151 and KNI-272 are excluded”.

 

Consequently, the P450 Psytochrome in claim 46 is not restricted to  the 3A4 enzyme. Nor is it restricted to the 3A4 enzyme in dependent claims 47 and 48.

Applicant finds support for the amendment on pages 2 and 3 of the specification where it is stated that:

“…It has been discovered that coadministration  of ritonavir with a drug which is metabolized by cytochrome P450 monooxygenase, especially the P450 3A4 isozyme, causes an improvement in the pharmacokinetics of such a drug.

In particular, it has been discovered that coadministration of ritonavir with an HIV protease inhibitor which is metabolized by cytochrome P450 monooxygenase causes  an unexpected improvement in the pharmacokinetics of such an HIV protease inhibitor”.

 Furthermore, 3A4 is specifically mentioned on page 10 of the specification:

“The ability of ritonavir to improve the cytochrome P450 monooxygenase activity was tested with terfenadine as the probe substrate (Yun et al., Drug Metabolism & Disposition, Vol 21 403-407 (1993)). Ritonavir inhibited the terfenadine hydroxylase activity representing the most abundant form of cytochrome P450 (CYP3A4) present in human liver with IC50 of 0.25 µM”

In short, the enzymes of the CYP 450 group of monooxygenase are part of a complex system that serves, inter alia, to destroy potentially poisonous materials such as drugs. These enzymes are found in high concentrations in the liver. Each enzyme acts on a specific molecule and on a specific site on the molecule. In the CYP450 group are many enzymes and this is one of the better known groups, and the CYP 3A4 is one such enzyme (as per Opinion of Krako, pages 2-3). 

The Opposers claim that the amendment is an attempt to rewrite the application retroactively and to switch the originally claimed invention with one not reasonably supported by the specification and not described. Furthermore, the new claims are alleged to be unclear and indefinite and thus contrary to Sections 12, 13 and 66 of the Law. The Opposers further accuse the Applicant of inequitable behaviour and of delaying tactics in filing the amendment.

Teva considers that the amendment submission should have been supported by an affidavit.

Vertex alleges that the amendment contravenes regulation 20(a)3 of the regulations 1968 since the Patent Specification does not teach restriction to the 3A4 enzyme rather than the entire CYP450 group. In the specification, the listed examples of drugs improved by Ritonavir includes those in the CYP450 group that are not within the CYP 3A4 family.  This is true of the drugs mentioned in the preferred embodiments as well. The specification does not mention which of the many drugs are taken in combination with Ritonavir are specifically metabolized by the CYP3A4 group and does not provide tools to persons of the art to understand the invention or to implement it.

DISCUSSION

Section 29 of the Law describes how an Application may be amended after its allowance.

29. After his application was accepted under this Article, the applicant may amend the specification in his application in the manner prescribed in Article Three of Chapter Four, as if he were a patent owner.

Article 3 of the Law defines the right to amend the specification thus

[Right to Amend]

65. A patent holder may apply to have the patent specification amended in order to clarify it, to eliminate a mistake in the specification or to restrict the claims.

[Condition of amendment]

66. The Registrar shall permit an amendment if he is satisfied that it will not result in a broadening of the scope of claims in the specification and will not add anything to the specification, which in essence was not included in it from the start; notice that permission for the amendment was granted shall be published in Reshumot.

[Opposition to amendment]

67. Any person may oppose before the Registrar the grant of permission to amend a specification; opposition shall be by delivery of a notice to the Registrar within three months after the notice of the grant of permission to amend was published.

[Grounds for opposition]

68. The following are the grounds for opposition to the grant of permission to amend:

(1) there is a reason why the Registrar was entitled to refuse permission to amend;

(2) the amendment does not achieve the purpose for which it was requested.

As previously established, the conditions listed in Section 65 and 66 should be read as accumulative, such that amendment of the specification requires all of the to be fulfilled. See for example IL 188066 Rafael vs. Elta 11 May 2015 and Brome Compounds vs. Albermarle 12 November 2014.

As established in Brome Compounds vs. Albermarle 12 November 2014, support for an amendment may be found in any part of the specification.

According to the Applicant, the requested amendment narrows the scope of monopoly requested and is in accordance with Sections 29 and 65 of the Law.

According to the expert opinions, the cytochrome P450 system is a very wide group of enzymes . According to TEVA, the 3A4 iso-enzyme mentioning in Page 2 is background only, and  the reference on Page 10 of the specification was under the heading “Inhibition of Cytochrome P450” and it describes an in vitro test that demonstrates how P450 may be inhibited by Ritonavir.

No pharmakinetic improvement of any drug by either P450 or 3A4 is described, and so there is no support for the requested amendment.

Prof Krako was cross-examiner (pages 6-8 of the 11 March 2014 protocol) and it transpires that there are six central / dominant enzymes in this wide group that are significantly involved in these processes.

According to Applicant, since all the known drugs are metabolized by 3A4 one can deduce that Ritonavir is also metabolized by the enzyme and so the requested amendment is based on the specification. The 3A4 enzyme is one of the most important of the CYP450 enzymes and is the main one in the human body.

Professor Krako testified on behalf of the Oposer that in his opinion, the Applicant had known that the 3A4 enzyme was present in a large concentration in the human body and that it constitutes about 28% of the P450 enzymes in the body, something that he considers strengthens the allegation that the Applicant gave 3A4 by way of example of the way that Ritonavir can inhibit P450 enzymes and is not limited to 3A4. Furthermore, since Taxol is mentioned in the application, as an embodiment in conjunction with Ritonavir,   that the Applicant did not cinsder it as a specific source for drugs that serve as a CYP3A4 substrate and noted that the metabolism of Taxol is mainly due to CYP2C8 which is another enzyme in the P450 group.

The Opponent wishes to conclude from this that the Application does not state an intent to limit the monopoly to 3A4 iso-enzymes specificallyץ

In response to these allegations. the Applicant noted that reading the specification together with Yunn et al. that is mentioned therein (page 10 of the specification) one can learn that metabolism of the 3A4 iso-enzyme is specifically considered.

The Applicant argued that since the 3A4 iso-enzyme is the dominant one of the P450 group one can understand the invention as being based on the 3A4 enzyme with the specification widening to include other species. The Applicant’s expert concurred that the applicant related to a wider group of enzymes such he believed that there are other enzymes in the CYP450 group that are active.

It was claimed that the specification relates to trials with various mammals lacking the 3A4 enzyme prior to 1995. Since the 3a4 iso-enzyme is only found in humans, the opposer concluded that the attempt to limit the specification of the 3A4 enzyme went beyond the scope of the specification.  In this regard it is noted that both expert witnesses concur that the 3A4 enzyme is only found in man, or at least is not found in laboratory animals and this fact was known when the application was filed.

Professor Danon, on behalf of the Applicant had to concur that the original wording of claim 1 from prior to the requested amendment claimed metabolism by the CYP450 enzymes and was thus not entirely accurate. However, he attributed this inaccuracy not to a mistake but rather to the fact that the whole time the intended application was to claim something that included the 3A4 enzyme and noted the IC50 as being  ‘critical’.

The expert witnesses disagree as to how persons of the art would understand the specification. From Professor Krako’s opinion, the Application is directed to the 3A4 iso-enzyme as one of a larger group of enzymes so a person of the art would understand mention of the 3A4 enzyme as simply an example of the inhibitory effect of cytochrome P450, whereas Professor Danon understands that a person of the art would understand that 3A4 is a specific example from the CYP450 group.

From the cross-examinations it appears that persons of the art would not discount the possibility that 3A4 is included in the group of enzymes that are inhibited by Ritonavir as part of the P450 group. At least, 3A4 is one of the enzymes that was tested in the framework of the tests reviewed in the application as part of the inhibition by cytochrome P450. Under cross-examination, Professor Krako reiterated that the inhibition in question is inhibition of the activity of Trepenadine Hydroxilase and even back when the testing took place there was doubt in the field as to whether Trepenadine Hydroxilase is 3A4 or not. In further cross-examination Professor Krako testified that 3A4  is the dominant enzyme our of the CYP 3A group.

Professor Danon testified that although the Applicant did not indicate in the original specification that the compounds mentioned undergo metabolism by the 3A4 enzyme, but the compounds selected were those that in fact are broken down by 3A4.

From the above there is a difference of opinion regarding what a person of the art would understand from the specification and whether one can conclude from the specification that the applicant intended processes that occur with CYP3A4 only.

The specification uses the words ‘especially’ and ‘abundant’ with respect to the 3A4 enzyme. This indicates that even prior to the proposed amendment the 3A4 enzyme was singled out.

Under cross-examination, Professor Danon attempted to argue that there was a difference between ‘the most dominant’ and ‘the most abundant’ as used in the specification. The latter implies that in comparison to other enzymes, its applicability is larger. Professor Krako did not dispute this but stood firm o the differences and  explained that the dominance of 3A4 in this connection is in comparison to other enzymes in the CYP3A family.

In the opposition to amending the specification of IL 101537 to Merck in Unipharm vs. Merck (30 April 2003) the then Deputy Commissioner (Yisrael Axelrod) related to the requirement of Section 66 of the Law and ruled that adding a species to a claim can be legitimate in a request to correct the specification. See paragraphs 22 and 27 of the specification:

“Al the above bring me to conclude that according to Section 66 of the Patent Law one can amend the specification of a patent or of a patent application published under Section 26 of the Law, by adding an additional element to the claims, so long as the element is essentially mentioned in the specification prior to the amendment. This works with the wording of the Section and with the underlying logic that permits narrowing amendments to the original claims. That is also in accordance with both local and foreign case-law.

Since 3A4 was understood as being the dominant enzyme in humans, limiting the claims to this enzyme is a narrowing of the scope of the claims. However, it must be noted that the requested amendment to claim 46 does not limit P450 to 3A4iso-enzymes only. The Opposer claims that lack of this narrowing is indicative of lack of unity and consistency. No one disputes that the amendment to claim 46 narrows the claim with respect to its original wording. Consequently there appears to be a prima facie case to allow the amendment.  Other aspects of the amendment can be considered within the framework of the main opposition.

The removal or the list of drugs claimed in the other claims is a limitation to the scope of the claims and is in accordance with Sections 65 and 66.

The commissioner then related to the other issues raised by the Opposers in response to the amended claims.

The Opposers claimed that the section quoted in Page 2, of the specification does not make a case that the invention is a combination of Ritonavir with drugs that are specifically metabolized by 3A4 iso-enzymes. They also claimed that one cannot learn from specification regarding the circumstances where the combination of Ritonavir with drugs that are specifically metabolized by 3A4 iso-enzymes improves the pharmaceutical efficacy of these drugs, or how to identify these drugs. In addition, TEVA pointed out that the application also does not teach this with regards to drugs metabolized by P450. Thus the Opposer alleges that the claimed invention lacks utility in that it does not do what it claims to.

In the ruling concerning the Refael opposition, section 39 states:

“So long as one of the desired results listed in Section 65 is achieved within the limitations of Section 66 of the Law that ensues that the amendment does not change the invention from that originally intended to be claimed, there is no reason not to allow the amendment.”

Also in the present circumstances, I do not think that these claims regarding efficacy of the invention and sufficiency of the specification are sufficient to warrant digressing from the requirements of Sections 65 and 66 of the Law. Generally, questions of efficacy and sufficiency of the specification  require factual inquiry and are not sufficiently developed by the parties to this opposition. The place for these issues is in the main opposition and not in the present skirmish interim procedure regarding proposed amendment. Had the Applicant discovered different efficacies and regarding the effect of different enzymes from within the group and the pharmakinetics of the drugs, then removing most of the listed enzymes from the claims would certainly be considered a narrowing of the scope of the claims. It will, however, be understood that this does not nail down the coffin lid with regards to efficacy or other questions that may arise in the opposition proceeding.

As mentioned previously, the Opposer has claimed unacceptable tardiness and a statute of limitations for making the desired amendment. The Opposer basically is taking the position that the Applicant knew that the invention was not efficacious across the claimed range of drugs and enzymes much earlier on (1998, 2001, 2005) by virtue of  parallel proceedings in the European Patent Office (EPO). In effect, the question of efficacy is tied to the question of tardiness. This needs additional clarification and it is preferably from legal perspective that the clarification is done on a narrower set of claims.

The question of tardiness in requesting claim amendments has been addressed in the past in the Unipharm decision, and it was established that this allegation is not sufficient reason not to allow the amendment so long as it cannot be concluded that the delay was based on inequitable behavior. Thus in Section 14 of the Unipharm ruling it is stated:

” The counsel for the Applicant is correct to claim that generally a request to amend the specification will not be rejected merely because it was submitted relatively late in the proceedings. Only if the Applicant has unclean hands (has behaved improperly) or has stood firm that the claims should not be amended in an unreasonable manner, is it proper to reject a request for amendment. See the American Cyanide decision pages 801-802.”

A tremendous amount of time has passed since the application was filed in Israel in 1996 and the request to amend the claims in 2013, which was after the statement of opposition was filed in 2012 and this can raise issues of inequitable behavior on the part of the Applicant who didn’t submit the request so as to have the amended claims considered over a long period.  Nevertheless, the request does narrow the scope of protection and is in accordance with sections 65 and 66 of the Law, it fulfills the purpose for which it was submitted and is thus in accordance with section 68(a) of the Law. Additionally, after the examination and acceptance of the original claims and with regards to the Applicants responses with respect to the prior art,  questions of tardiness  and efficacy do need does not seem to be sufficient grounds to prohibit the amendment.

The questions that may be raised regarding alleged inequitable behavior may be considered in the opposition itself or in other proceedings, See 33666-07-11 Unipharm vs. Sanofi et al. 8 October 2015. 

In conclusion, the request to amend the specification was approved. The amendment will be published for opposition purposes in accordance with Section 97 of the regulations.

Since the maximum patent term of Section 52 is close to the current date, the parties are given 10 days to explain how the opposition can be continued and whether agree that the commissioner can continue to manage an opposition to a patent issuing after more than 20 years from filing has passed.

Expenses to be awarded for the current skirmish will be awarded in the main award for the opposition.

Opposition to IL 122546 to Abbvie Inc. by Teva and Vertex, interim ruling by Asa Kling,  2 May 2016

 

 

 

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