DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application is a 371 of PCT/US2021/030950, filed May 5, 2021, which claims the benefit of an effective US filing date from provisional application 63/020,904, filed May 6, 2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on October 27, 2023 and December 17, 2025 were in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the IDS documents were considered and signed copies of the 1449 forms are attached.
Election/Restrictions
Applicant’s election without traverse of Group I (compounds of Formula (II) where Y1 is a spirocyclic moiety), in the reply filed on December 17, 2025 is acknowledged. Further, Applicant’s election of Compound 110
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in the same reply is also acknowledged.
Upon further consideration, it was found that no prior art anticipates or renders obvious the formula II, as presently amended, which is the technical feature of the instant claims. Thus, the amended claims are found to possess unity of invention and the restriction requirement made under lack of unity practice is withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Status of the Claims
Currently, claims 1, 3, 6, 9, 17-20, 23, 25, 27, 29-33, 35, 37, 39, 41, 50, 52, 54-56, 58, 60, 62-63, 85, 89, 92, 94, 96 and 100-102 are pending in the instant application and under consideration herein.
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.
Claim 102 is 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 treating diseases and conditions for which a clear nexus between NAMPT activation and disease treatment has been established does not reasonably provide enablement for
The definition of “treatment” as presently recited, which includes prevention or prophylaxis of the entire list of claimed conditions, many of which are well established as not being preventable; or
the full scope of incredibly broad diseases, which include (without limitation) all cancers, all neurodegenerative conditions, all inflammatory conditions, all cardiac conditions, aging and many more.
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. Applicant has not provided sufficient evidence to enable one of skill in the art to practice the full scope of the instant invention without undue experimentation. Support provided by the applicant is enabling for the modulation of NAMPT (see Example A), as well as treatment (in a subject already having the disease) of particular conditions known to have an established nexus with the neuroblastoma SH-SY5Y cell line tested in Example B (for example, Parkinson’s disease and Alzheimer’s disease).
As a general rule, enablement must be commensurate with the scope of claim language.MPEP 2164.08 states, "The Federal Circuit has repeatedly held that "the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation." In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)" (emphasis added). The "make and use the full scope of the invention without undue experimentation" language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: "A lack of enablement for the full scope of a claim, however, is a legitimate rejection." The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc., 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int'l, Inc. v. BMWofN. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
In evaluating the enablement question, several factors are to be considered. Note In re Wands, 8 USPQ2d 1400 and Ex parte Forman, 230 USPQ 546. The factors include: 1) The nature of the invention, 2) the state of the prior art, 3) the predictability or lack thereof in the art, 4) the amount of direction or guidance present, 5) the presence or absence of working examples, 6) the breadth of the claims, and 7) the quantity of experimentation needed. The determination that “undue experimentation” would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations.
The nature of the invention and breadth of claims
Claim 1 is drawn to compounds regarded as Formula (II) (see [0008]-[0067] of the specification). The specification teaches compounds of the invention inhibit NAMPT (see [0002], method of inhibiting NAMPT with these compounds).
Notably, the term “treatment” and related terms is interpreted in a manner consistent with the specification, which specifically defines the term as inclusive of preventing the disease or disorder in an individual not yet having the disease (paragraph [0166]).
Claim 102 depends from claim 1 and recites a method of treating a disease or condition is selected from the group consisting of cancer, a hyperproliferative disease or condition, an inflammatory disease or condition, a metabolic disorder, a cardiac disease or condition, chemotherapy induced tissue damage, a renal disease, a metabolic disease, a neurological disease or injury, a neurodegenerative disorder or disease, diseases caused by impaired stem cell function, diseases caused by DNA damage, primary mitochondrial disorders, a muscle disease or muscle wasting disorder, or a disease or condition is selected from the group consisting of obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve damage, polio (poliomyelitis), and spinal cord injury.
The specification, however, does not provide a closed list of diseases included in the scope of the instant method. Nor does the specification define the cancers, hyperproliferative diseases, inflammatory diseases, cardiac disease, renal diseases, neurodegenerative diseases, etc. which are necessarily mediated through the NAMPT pathway.
The nature of the invention is thus regarded as a method of treatment of and incredibly broad list of diseases comprising administration of a compound of Formula (II) wherein the compounds treat the disease by inhibiting NAMPT. Because applicant has not provided a listing of diseases included in the scope of the claims, the claims are regarded as being drawn to treating any cancer, any inflammatory disease, any neurodegenerative disease, etc. known in the art.
The state of the prior art
No compound has ever been found to treat cancers of all types generally. Since this assertion is contrary to what is known in medicine, proof must be provided that this revolutionary assertion has merits. The existence of such a “silver bullet” is contrary to our present understanding of oncology. The state of the art is not indicative any pharmaceutical agents that are useful in the treatment of cancer generally. Cecil Textbook of Medicine states that “each specific type has unique biologic and clinical features that must be appreciated for proper diagnosis, treatment and study” (see the enclosed article, page 1004). Different types of cancers affect different organs and have different methods of growth and harm to the body. Also see In re Buting, 163 USPQ 689 (CCPA 1969), wherein 'evidence involving a single compound and two types of cancer, was held insufficient to establish the utility of the claims directed to disparate types of cancers'. Thus, it is beyond the skill of oncologists today to get an agent to be effective against cancers generally.
A similar statement appears at In re Application of Hozumi et al., 226 USPQ 353: “In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way”. There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers.
The attempts to find compounds to treat the various cancers arguably constitute the single most massive enterprise in all of pharmacology. This has not resulted in finding any treatment for tumors generally. Indeed, the existence of such a "silver bullet" is contrary to our present understanding in oncology. This is because it is now understood that there is no “master switch” for cancers generally; cancers arise from a bewildering variety of differing mechanisms. Even the most broadly effective antitumor agents are only effective against a small fraction of the vast number of different cancers known. This is true in part because cancers arise from a wide variety of sources, primarily a wide variety of failures of the body's cell growth regulatory mechanisms, but also such external factors such as viruses (an estimated at least 20% are of viral origin e.g. Human papillomavirus, EBV, Hepatitis B and C, HHV-8, HTLV-1 and other retroviruses, and quite possibly Merkel cell polyomavirus, and there is some evidence that CMV is a causative agent in glioblastoma), exposure to chemicals such as tobacco tars, excess alcohol consumption (which causes hepatic cirrhosis, an important cause of HCC), ionizing radiation, and unknown environment factors.
Similarly, In re Novak, 134 USPQ 335, 337-338, says “unless one with ordinary skill in the art would accept those allegations as obviously valid and correct, it is proper for the examiner to ask for evidence which substantiates them.” There is no such evidence in this case for a compound that treats all types of cancer. Likewise, In re Cortright, 49 USPQ2d 1464, states: “Moreover, we have not been shown that one of ordinary skill would necessarily conclude from the information expressly disclosed by the written description that the active ingredient” does what the specification surmises that it does. That is exactly the case here. Moreover, even if applicants’ assertion that cancer in general could be treated with these compounds were plausible --- which it is not ---, that “plausible” would not suffice, as was stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297, 1301: “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success.”
Recently, Wu (Journal of Hematology & Oncology 2022 (15) 143) discloses that between 1991 and 2021 there have been 228 new cancer drugs approved by the U.S. Food and Drug Administration of which 120 of these are drawn to the treatment of solid tumors alone (Abstract). Wu teaches that there are 21 different approved drugs for treating lung cancers, some of which have different cellular targets (Table 1, page 5). Similarly, breast cancer (see Table 2, page 10) has 22 different drugs that have varied cellular targets and are indicated for different types of breast cancer. More still, Table 4 (page 17) indicates that there are 17 different drugs available to treat different forms of gastrointestinal cancers. See also Table 6 (page 25), drugs approved for urologic cancers, Table 7 (page 28), drugs approved for skin cancers, and Table 8 (page 33), drugs approved for thyroid cancer. Wu further provides an illustration summarizing the protein structure of some cellular targets and the binding site of their respective drugs (Fig 12, page 38). Taken as a whole, Wu teaches that no single therapeutic has ever been identified as a treatment for all forms of cancer; and closer examination of Fig 12 provides a logical explanation: As highlighted in Fig 12, molecular protein targets implicated in different cancers (e.g. EGFR for lung cancer (see Table 1), VEGFR2 for gastric cancer (see Table 4)) have different three-dimensional protein structures, different active sites, and therefore require different drugs with the right shape and chemical groups in order to bind the target active site and have an effect in treating the cancer. In other words, there is no one size fits all approach to treating cancer simply for the reason that no single molecule will have the shape and chemical functional groups necessary to bind and modulate all molecular targets of cancer, all of which all have varied shapes. It is commonly known in the pharmaceutical arts that shape dictates function wherein drugs which have a shape complimentary to the protein target will bind and have an effect (this is often referred to simplistically as a “Lock and Key” model). Given the varied shape of protein targets in cancer (e.g. EGFR and VEGFR2), it is pure fantasy to speculate that a single drug with a single three dimensional shape will bind all protein targets implicated in cancer therapy and have an effect in treating all forms of the disease. As such, at present the “silver bullet” drug therapy to treat all forms of cancer is elusive and such a therapy is not recognized in the art where the reality is that different forms of cancer require different drug therapies (see Wu).
Similar analyses can be made on the diseases encompassed by the additional broad classes of diseases included in the claimed scope, as no single compound has ever been found useful for treating all neurodegenerative, all cardiac, all renal disease, etc.
Predictability in the art:
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 statute. Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved”. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Applicant has not provided a nexus between the disclosed biological assays and the treatment of all cancers. The biological data provided in the specification in itself is not sufficient to enable the instant claims encompassing a method of treating cancer as broadly as is claimed. Applicant has not provided any competent evidence or disclosed tests that are highly predictive for the pharmaceutical use of the instant compounds.
The Level of One of Ordinary Skill
The level of skill in the art is high.
Amount of guidance/working examples:
Applicant teaches compounds of the invention are inhibitors of NAMPT (see Table A, Biological Example 1). Applicant further provides data to show the compounds of the invention stimulate endogenous NAMPT in neuroblastoma SH-SY5Y cells (see Biological Example 1, Table B).
Applicant, however, has not presented any evidence that the disclosed models of in vitro assays are art-recognized models which are representative of all types of cancer, neurodegenerative conditions, hyperproliferative diseases, etc. and further, that the assays are useful in establishing the preventative activity of the invention compounds for the prevention of disease in otherwise healthy individuals.
Simply put, the specification does not provide any guidance to one of ordinary skill in the art to extrapolate the biological data to the treatment and prevention of an incredibly broad list of diseases that affect different organs and/or have diverse mechanisms. As the Supreme Court said in Brenner v. Manson, 148 USPQ at 696: “a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.” As U.S. Court of Customs and Patent Appeals stated In re Diedrich 138 USPQ at 130, quoting with approval from the decision of the board: “We do not believe that it was the intention of the statutes to require the Patent Office, the courts, or the public to play the sort of guessing game that might be involved if an applicant could satisfy the requirements of the statutes by indicating the usefulness of a claimed compound in terms of possible use so general as to be meaningless and then, after his research or that of his competitors has definitely ascertained an actual use for the compound, adducing evidence intended to show that a particular specific use would have been obvious to men skilled in the particular art to which this use relates.”
The quantity of experimentation needed:
MPEP 2164.01(a) states, "A conclusion of lack of enablement means that, based on theevidence regarding each of the above factors, the specification, at the time the application was filed, 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)." Because the guidance and teaching provided by the specification is insufficient for using the instant method, that conclusion is clearly justified here and one of ordinary skill in the art, even with high level of skill, would have to undergo an undue amount of experimentation to use the invention.
Applicant is encouraged to submit any supporting evidence to show the instant method works in the treatment and prevention of diseases as is broadly claimed, or amend the claims as indicated in this rejection. It is suggested that to overcome the recitation of “prevention” in the definition of “treatment” in the specification, the claim may be limited to treatment of patients already having the diseases as claimed, in combination with an amendment to narrow the scope of diseases to those with an established nexus to NAMPT activation, for which enablement has been demonstrated.
Allowable Subject Matter
Claims 1, 3, 6, 9, 17-20, 23, 25, 27, 29-33, 35, 37, 39, 41, 50, 52, 54-56, 58, 60, 62-63, 85, 89, 92, 94, 96 and 100-101 are allowed.
The closest prior art to the instantly claimed compounds is US 20130109668 (cited on 10/27/2023 IDS). The compounds of the prior art differ in several key respects, including an extra substituent on the R1 phenyl group, in addition to the R2a substituent. There is no teaching or suggestion in the reference which would have motivated a person skilled in art to modify these compounds into the instant invention with any reasonable expectation of success. Furthermore, the prior art compounds have a different utility, such that there would have been no expectation of obtaining compounds with utility as NAMPT modulators. Accordingly, the claimed compounds are allowable.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alicia L. Otton whose telephone number is (571)270-7683. The examiner can normally be reached on Monday - Thursday, 8:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mr. Fereydoun Sajjadi can be reached on 571-272-3311. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALICIA L OTTON/Primary Examiner, Art Unit 1699