ALLOWANCE
This action is in response to Applicant’s submission dated February 7, 2024, in which Applicant canceled claims 1-10 and amended claim 11 to remove the first six compounds. Claim 11 is allowed for reasons of record.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over CN 113735862 in view of US 6,603,008, US 6,221,335, US 2007/0082929, US 2007/0197695, US 7,517,990, Tonn, Haskins, Wolen, Browne, Baillie, US 6,440,710, Gouyette, Cherrah, Pieniaszek, and Honma et al.
Determining the scope and contents of the prior art.
CN 113735862, which discloses compound GS-441524 at paragraph [0135]:,
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but the above-mentioned compound does not contain a deuterium atom or contains a deuterium atom at a position different from the position of the deuterium atom in claim 11. The rejected claim differs from the primary reference in that the claimed compound is deuterated. The secondary references teach that such a modification is obvious, for two separate reasons.
First, one is motivated to prepare deuterated versions of drugs to obtain a version with better pharmaceutical properties.
US 6,603,008 teaches "[S]ubstitution with heavier isotopes such as deuterium, i.e. 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances". See col. 6, lines 59-67 and col. 7, lines 11-16.
US 6,221,335 teaches that “by deuterating drugs, we have likely … increased the lipophilic nature of the molecule” and, via the deuterium isotope effect, produced a derivative “less easily cleaved by metabolic (or destructive) processes. Hence, the elimination half life of the drug is prolonged and the drug's therapeutic effects are increased.”
US 2007/0082929, paragraph 0014 states, “Deuteration of pharmaceuticals to improve pharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles, has been demonstrated previously with some classes of drugs.
US 2007/0197695 states, “Deuteration can yield pharmaceuticals having improved bioavailability and reduced the toxicity.”
US 7,517,990 states, “a deuterated compound is very useful in elucidation of reaction mechanism and substance metabolism and used widely as a labeled compound. Said compound is also known to be useful as drugs, pesticides … and the like due to change in stability and property itself by isotope effect thereof.”
Second, and as an alternative branch, one is motivated to prepare deuterated versions of drugs, which can be used to obtain valuable information about how the un-deuterated drug or closely related drugs act in the body. Note the quotation for US 7,517,990 supra. In addition:
Tonn, Biological Mass Spectrometry Volume 22 Issue 11, Pages 633 – 642 (1993) states: “Pharmacokinetic studies employing stable isotope labeled drugs… offer many advantages over the more conventional use of unlabeled drugs… A pharmacokinetic study in which a labeled and an unlabeled drug are simultaneously and independently … is advantageous since it reduces to inter-day variability in the measured pharmacokinetic parameters. The advantages of this approach include an increase in the statistical power of the study, yielding an overall reduction in the number of study subjects, and also a diminished risk due to a reduction in the exposures to the drug. In addition, the overall time required to conduct experiments, and hence the number of samples to be collected for analysis, may also be substantially reduced.” The reference study is an example of just that. Thus, one is motivated to prepare deuterated drugs to gain these explicitly set forth advantages.”
Haskins, Biomedical Spectrometry Vol. 9 Issue 7, pp. 269 – 277 (1982) surveys the application of stable isotopes in biomedical research in several areas. For example, in stable isotope dilution assays, it notes that deuterium “is the best heavy isotope for this work”. Also, the section on the use of stable isotopes in chronic administration studies lists only deuterium isotopes.
Wolen, J. of Clinical Pharmacology 1986; 26: 419-424, noting that the lack of toxicity for deuterium makes it “ideally suited for human studies” (abstract) concludes that “the application of stable isotope methodology to the problems of bioavailability and bioequivalence have proved extremely versatile and useful. The technique is simple and powerful and results in extremely low risk to the subject" at 423. Thus, one is motivated to prepare deuterated drugs to gain these advantages.
Browne, J. of Clinical Pharmacology, 1998; 38: 213-220 quantifies the advantage of using stable isotope labeled drugs to, for example, identify metabolites, to evaluate drug interactions, and to measure absolute bioavailability. Compared with standard methods which do not use isotopically labeled drugs, there is a cost reduction of 23% and a reduction in 36% in terms of the number of subjected needed. This again provides a strong motivation, to obtain these advantages.
Baillie, Pharmacology Rev.1981; 33: 81-132 is a useful review of the use of stable isotopes. For example, pages 108-110 (section III C1) discuss the use of deuterated compounds in mechanism and toxicology studies, on drugs such as cyclophosphamide, iproniazid, and ibuprofen. Pages 114-117 (section II C 4) discuss the use the deuterium isotope effect to understand the metabolism of drugs such as chloroform and other inhaled anesthetics, furosemide, and caffeine.
US 6,440,710 states, “Deuterium- and tritium-labeled organic compounds have become increasingly important for the role they play in structure determination, mechanistic studies, elucidation of biosynthetic pathways and in biochemical studies.”
Gouyette, Biomedical And Environmental Mass Spectrometry, Vol. 15, 243-247 (1988), gives an example with the anti-cancer drug Elliptinium. The reference notes: “New derivatives in the ellipticine series are under preclinical and clinical development. In order to study the fate of those molecules, it was decided that a standard molecule of this family of intercalating agents be labelled with stable isotopes which might be used in man without any problem of radioprotection or irradiation. Therefore, in a first step, elliptinium was labelled with three deuterium atoms, then injected intravenously into rats…” In this way, they were “able to confirm the presence of unchanged drug in urine and in bile” and identify two metabolites. This information provided about ellipticine is relevant to other derivatives in the ellipticine series.
Another example is Cherrah, Biomedical and Environmental Mass Spectrometry Volume 14 Issue 11, Pages 653 - 657 (1987), which teaches the use of deuterated Xanthines to study the binding of Xanthines to human serum albumin.
Pieniaszek, J Clin Pharmacol.1999; 39: 817-825 is an example showing the use of a deuterated drug (an agent for treating ventricular arrhythmia) to determine bioavailability in a technique which necessitated far fewer subjects, fewer blood collections and lower clinical costs. See page 824, column 2.
Honma et al., Drug Metab. Dispos. 15 (4): 551 (1987) employed a combination of both stable and radioactive isotope-labeled analogs to determine the metabolic fate of Roxatidine acetate hydrochloride, including the chemical structures of its metabolites, and the specific sites of metabolic attack. See page 556.
These last five references are merely exemplary of the use of deuterated compounds to determine valuable information about pharmaceuticals and their analogues; there are many other such references.
Ascertaining the difference between the prior art and the claims at issue.
The present claims disclose:
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where exactly one hydrogen atom of compound GS-441524 is replaced by a deuterium atom. The primary reference differs from the present invention in that none of the hydrogen atoms are replaced by a deuterium atom.
Resolving the level of skill in the art.
Hence, it is clear that “a person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and that there would have been a reasonable expectation of success." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641, 1645.
Moreover, given that there is always a need to enhance the pharmacological effects of a compound (e.g. increased in vivo half-life) without significantly altering its basic chemical structure, or that there is always a need to reduce the time, cost, risk, and statistical imprecision of pharmacokinetic studies (e.g. measure bioavailability or identify metabolites), and that there is only a limited number of ways that this can be done, it would be obvious to pursue a potential solution that has a reasonable expectation of success. See e.g. KSR Int’l Co. v. Teleflex Inc., 1385, 1397; Pfizer, Inc. v. Apotex, Inc., 82 USPQ2d 1321; Alza Corp. v. Mylan Laboratories, Inc., 80 USPQ2d 1001; In re Kubin, 90 USPQ2d 1417; In re O’Farrell, 7 USPQ2d 1673, 1681; In re Eli Lilly & Co., 14 USPQ2d 1741; In re Ball Corp., 18 USPQ2d 1491.
In addition, it is clear that deuteration per se is a known improvement technique for getting a more useful version of the pharmaceutical, and that the improvement is of a predictable nature, as is seen by the success reported in the various secondary references. Thus, it would have been obvious to one of ordinary skill in the pharmaceutical art to have applied this known improvement technique in the same way to the compound of the primary reference to obtain the results reasonably predictable from the secondary references. See e.g. KSR Int’l Co. v. Teleflex Inc., 1385, 1396; Ruiz v. AB Chance Co., 69 USPQ2d 1686; In re Nilssen, 7 USPQ2d 1500.
Selecting and optimizing the level of deuteration, up to an including full deuteration, would be within the skill of one seeking to achieve either of the goals set forth in the secondary references. For example, setting 100% deuteration at one position is routinely done, and as seen by the references cited above.
Accordingly the rejected claims are deemed obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ERICH A LEESER whose telephone number is (571) 272-9932. The Examiner can normally be reached Monday through Friday from 10-6 PST, M-F. PST.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Mr. James Alstrum-Acevedo can be reached at (571) 272-5548. The fax number for the organization where this application is assigned is 571-273-8300.
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/ERICH A LEESER/Primary Examiner, Art Unit 1622
United States Patent and Trademark Office
Tel. No.: (571) 272-9932
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