Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Claims 1-20 are pending and under consideration in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/16/2024 (2) complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits. See attached copy of the PTO-1449.
Priority
This application is a continuation of U.S. Application No. 17/219,176, filed March 31, 2021, which is a continuation of U.S. Application No. 16/454,174, filed on June 27, 2019, now abandoned, which is a continuation of U.S. Application No. 15/718,666 filed on September 28, 2017, now abandoned, which is a continuation of U.S. Application No. 14/764,836, filed on July 30, 2015, now abandoned, which is a national stage 371 application of PCT/US2014/013327, filed on Jan. 28, 2014, which claims the benefit of priority of United States provisional application No. 61/758,861, filed January 31, 2013.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.-The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 14-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the claimed compounds in the method of binding VMAT2 , does not reasonably provide enablement for treating any disorder mediated by VMAT2. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue". These factors include
1) the breadth of the .claims, 2) the nature of the invention, 3) the state of the prior art, 4) the level of one of ordinary skill, 5) the level of predictability in the art, 6) the amount of direction provided by the inventor, 7) the existence of working examples, and 8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
1) Nature of the invention and The breadth of the claims :
The instant claims are drawn to a method of treatment of a VMAT2-mediated disorder comprising the administration, to a patient in need thereof, of a therapeutically effective amount of the compounds encompassed by Formula II shown below, with variables as defined in the claims
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VMAT2 mediated disorder includes chronic hyperkinetic movement disorders, Huntington's disease, hemiballismus, chorea associated with Huntington's disease, senile chorea, tic disorders, tardive dyskinesia, dystonia, Tourette's syndrome, depression, cancer, rheumatoid arthritis, psychosis, multiple sclerosis, asthma, Parkinson's disease levodopa-induced dyskinesia, movement disorders, and oppositional defiant disorder.
2)The state of the prior art, Relative skill in the art and the level of predictability in the art:
The state of the prior art is that it involves screening in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities. There is no absolute predictability and no established correlation between in vitro activity and the treatment of diseases as the in vitro data is not a reliable predictor of success even in view of the seemingly high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic regimen on its face.
The known drug tetrabenazine is used for treating hyperkinetic movement disorders. So one would expect a similar compound to have that activity. However there is nothing to show that it can treat any disorder.
It is noted that the pharmaceutical art is unpredictable requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F. 2d 833, 166 USPQ 18(CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statue. The level of unpredictability is in the art is very high. The compounds which differ by a methyl group also show different properties, for e.g. theophylline and caffeine. One of them is a bronchodilator and they differ only by a methyl group. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.), Nationwide Chemical Corporation, et al. V. Wright, et al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances), Ex parte Sudilovsky 21 USPQ2d 1702 (Appellant's invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable) In re Wright 27 USPQ2d 1510 physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian recombinant virus vaccine was uncertain).
Taking Huntington disorder for e.g. Huntington' s disease is an inherited disease conditioned by abnormal movements, dementia and psychiatric problems. Hyperkinesis is just one of the symptoms of Huntington disorder. Huntington disease involves progressive loss of mental function, including personality changes and loss of cognitive functions such as judgment and body movements develop, including quick jerking movements and lists a number of symptoms on page 1 and 2 ). There is no known cure for Huntington' s disease and there is no way to stop the progression of the disorder, the treatment is aimed at maximizing the ability to function as long as possible (Page 2, under treatment section). It is the similar situation with Parkinson’s disease too.
“[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.” As discussed above, the instantly claimed invention pertains to method of treating VMTA2 mediated disorders which are alleged by the Specification to be useful for that purpose. At the time the instant application was filed, it would have been known by those of ordinary skill in the art that due in large part to the strict requirement of complementarity between a compound and its corresponding binding site on a target receptor or enzyme - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. At the same time, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects. Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity, etc.) would interact with the given target to elicit a related biological response. The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicants' invention would generally be a neurologist or neurobiologist. That factor is outweighed, however, by the unpredictable nature of the art. It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.), Nationwide Chemical Corporation, et al. v. Wright, et al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances), Ex parte Sudilovsky 21 USPQ 2d 1702
4) The amount of direction provided and existence of working examples:
The inventor provides no data in the specification to show that all these various disorders can be treated. The instant specification does not have any working examples nor is there a nexus provided to show that all and any disorder can be treated. Applicants reference to various articles for different assays (see instant specification [00159-00172]). It is noted that none of these assays involve assays which specifically studies the activity of these specific compounds on the various VMTA2 mediated diseases.
Absence of working examples is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP 2164.
5) The quantity of experimentation needed to make or use the invention based on the content of the disclosure: In view of all the above factors, guidance and state of the art, it would require an undue amount of experimentation to use the invention of the claims with to treat any diseases.
Taking the above factors into consideration, it is not seen where the instant specification enables the ordinary artisan to make and/or use the instantly claimed invention.
Genetech Inc Vs Nova Nordisk 42 USPQ 2d 1001. "A patent is not a hunting license. It is not a reward for search but compensation for its successful conclusion and patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable."
MPEP 2164.01(a) states, "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was flied, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." That conclusion is clearly justified here. Thus, undue experimentation will be required to practice Applicants' invention.
Claim Rejections - 35 USC § 102(b)
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claim 1 is rejected under 35 U.S.C. 102(b) as being anticipated by Gant et al. (US 2012/0003330) (reference cited in the instant IDS)
Instant claims are drawn to a compound of structural formula II
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or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R1-R19 and R21-R39 are independently selected from the group consisting of hydrogen and deuterium; at least one of R1-R19 and R21-R39 is deuterium.
Gant et al discloses benzoquinolone inhibitor of VMAT2 of the following formula
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R1-R19 and R21-R29 are independently selected from the group consisting of hydrogen and deuterium; R20 is selected from the group consisting of hydrogen, deuterium, --C(O)O-alkyl and --C(O)--C1-6 alkyl, or a group cleavable under physiological conditions, wherein said alkyl or C1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of --NH--C(NH)NH2, --CO2H, --CO2alkyl, --SH, --C(O)NH2, --NH2, phenyl, --OH, 4-hydroxyphenyl, imidazolyl, and indolyl, and any R20 substituent is further optionally substituted with deuterium; and at least one of R1-R29 is deuterium or contains deuterium (Reference claims 1-41, and [0015-0018]. The limitations of the stereoisomers is disclosed by Gant et al. [0044] and the extent of deuteration is set forth in their claims 4-7. The substituents for R20 is disclosed by a small number of options and as such all the compounds encompassed can be clearly envisioned.
Accordingly claim 1 is anticipated by Gant et al.
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 nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-20 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Gant et al. (US2012/0003330, hereinafter referred to as ‘330) in view of Gant et al. (US 8524733 ‘733 hereinafter) and Gano et al. (WO 2008/058261) further in view of Ando et al. (US 6603008), Foster (US 6,221,335), Ito et al. (US 7,517,990) and Wolen, Journal of Clinical Pharmacology 1986; 26: 419-424) (references cited in the instant IDS)
Instant claims are drawn to a compound of structural formula II
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or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R1-R19 and R21-R39 are independently selected from the group consisting of hydrogen and deuterium; at least one of R1-R19 and R21-R39 is deuterium. Claims 14-20 are drawn to a method of treating VMAT2 mediated disorder with these compounds.
‘’330 discloses benzoquinolone inhibitor of VMAT2 of the following formula
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R1-R19 and R21-R29 are independently selected from the group consisting of hydrogen and deuterium; R20 is selected from the group consisting of hydrogen, deuterium, --C(O)O-alkyl and --C(O)--C1-6 alkyl, or a group cleavable under physiological conditions, wherein said alkyl or C1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of --NH--C(NH)NH2, --CO2H, --CO2alkyl, --SH, --C(O)NH2, --NH2, phenyl, --OH, 4-hydroxyphenyl, imidazolyl, and indolyl, and any R20 substituent is further optionally substituted with deuterium; and at least one of R1-R29 is deuterium or contains deuterium (Reference claims 1-41, and [0015-0018]. The limitations of the stereoisomers is disclosed by Gant et al. [0044] and the extent of deuteration is set forth in their claims 4-7. The substituents for R20 is disclosed by a small number of options and as such all the compounds encompassed can be clearly envisioned.
Gano et al. discloses the undeuterated form NBI-98854
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And discloses this compounds as dihydrotetrabenazine which is a prodrug of tetrabenazine (see pages 1-2 of the disclosure).
Gant et al. ‘733 disclose the deuterated compounds of the formula (col.3) and therefore teaches the genus which includes the applicants compounds,
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With the following compound: (reference claim 1)
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Gano et al. fails to disclose the compound which is deuterated and Gant et al. does not teach the instantly claimed specific compounds
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instead of = O,
The rejected claims differ 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
Ando et al 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).
Foster 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.”
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.
Ito et al. 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.”
Wolen, Journal 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.” (page 423) Thus, one is motivated to prepare deuterated drugs to gain these advantages.
Hence, it is clear that under either of these two branches, “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 (first branch), 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) (second branch), 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 International 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 under both branches 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 International Co. v. Teleflex Inc., 1385, 1396; Ruiz v. AB Chance Co., 69 USPQ2d 1686; In re Nilssen, 7 USPQ2d 1500. Accordingly the rejected claims are deemed obvious.
Some dependent claims specify various levels of deuteration. 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, di-deuteration and higher levels are also employed.
As such a person of ordinary skill in the art would be imbued with a reasonable expectation of success in that substituting deuterium to a hydrogen atom in a pharmacologically active compound would yield a similarly acting if not better acting compound with same mechanism but with higher stability and bioavailability, absence of evidence to the contrary. Further, Since the prodrug NBI-98854 is known and many deuterated forms and information about the deuterium kinetic isotope is also known, one of skill in the art would have been motivated to make the deuterated amino prodrug compounds. Since the other deuterated species were made , one would have been motivated and have a expectation of success at making the deuterated form of the C=O-alkanediyl amine taught by Gano et al. A person of ordinary skill in the art would be imbued with a reasonable expectation of success making such a compound absence of evidence to the contrary.
Conclusion
Claim 1-20 are rejected. No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAVITHA RAO whose telephone number is (571)270-5315. The examiner can normally be reached on Mon-Fri 7 am to 4 pm..
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached on (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAVITHA M RAO/Primary Examiner, Art Unit 1691
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