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 .
Status of Claims
The amendments to the claims filed June 29, 2023 are acknowledged and entered. Claims 1-15, 17-19 and 21-22 are pending.
Specification
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any of the errors of which applicant may become aware of in the specification.
Priority
This application is a 371 of PCT/US2021/065629, filed December 30, 2021, which claims the benefit of 63/132,798, filed December 31, 2020.
Information Disclosure Statement
Examiner notes that no IDS has been submitted in the present application and kindly reminds Applicant of the following: Applicants and other individuals substantially involved with the preparation and/or prosecution of the application have a duty to disclose to the office all information known to that individual to be material to patentability as defined in 37 CFR §1.56.
Claim Objections
Claims 21-22 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim should refer to other claims in the alternative only. See MPEP § 608.01(n). Presently, The claims depend indirectly from claim 1; however, the claims also require a composition of claims 2 or 7. Accordingly, the claim have not been further treated on the merits.
Claim Rejections - 35 USC § 112a
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 17 and 19 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 treating breast cancer or viral infection caused by HCMV does not reasonably provide enablement for
Treating cancer generally; or
Treatment or prevention of viral infection generally, including coronavirus
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 the instant case, inhibition of SIRT2 is not known as a general strategy for treating all diseases of the instant claims, least of all as a general treatment for all cancers. Applicant’s disclosure is only enabling for the treatment of conditions which Applicant has demonstrated may be treated by the instant compound, and of specific conditions which the art is aware can be treated by inhibition SIRT2 and for which Applicant has written support. Case law is clear on this point. In an unpredictable art, such as drug therapy to treat disease, models may be used for enablement only if there is a well-established correlation between the assay and clinical efficacy. Applicants have not demonstrated nor have they alleged there is any correlation between the in vitro assays they disclose demonstrating activity against breast cancer (Figures 1-8) and HCMV (pages 56-57) and clinical efficacy against all diseases included in the scope of the claims. No evidence is submitted that Formula (I) has any activity against any other cancer or virus (e.g. coronavirus) which are distinct from both breast cancer and HCMV. Given the direction provided by Applicant, one skilled in the art could not practice the full scope of the invention without undue and unreasonable experimentation.
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 & breadth of claims:
Claim 1 is drawn to a composition comprising a compound of Formula I. The specification teaches Formula I is an inhibitor of SIRT2 (see page 5, compounds of the invention are SIRT2 inhibitors)
Claim 17 depends from claim 1 and is drawn to a method of treating cancer in a patient in need of treatment comprising administering to said patient a therapeutically effective amount of a composition of claim 1.
Claim 19 depends from claim 1 and is drawn to a method for treating or preventing a viral infection in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition of claim 1.
The specification does not provide a definition of a “viral infection” or “cancer”.
The nature of the invention is a method of treating or preventing viral infection, or treating cancer, in a subject by administration of a SIRT2 inhibitor. The scope of the claims includes those cancers and viral infections explicitly recited by Applicant as well as any form of cancer or viral infection known in the art. The breadth of the claims is incredibly broad.
The state of the prior art
Treatment of Cancer
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, the state of the prior art and current state of the art are not aware of any “silver bullet” drug therapy to treat all forms of cancer as is claimed presently, at least for the reason that persons skilled in the art recognize that different forms of cancer have different treatment requirements and therefore require different drug therapies.
Treatment or Prevention of Viral Infection
The state of the prior art is not aware of any single agent that treats all viral infections generally. This is because different viral infections are caused by distinct viruses that have different modes of infection and therefore require different antiviral agents. Gelderblom (Medical Microbiology, CH 41, Structure and Classification of Viruses, 1996) teaches more than 30,000 different virus isolates are known today and grouped in more than 3,600 species, in 164 genera and 71 families, and of these families and genera, 21 are of known medical importance (page 4, virus classification). Figure 41-6 distinguishes between RNA and DNA viruses and illustrates that this subset of 21 viruses known to infect humans are distinct. Coronavirus, for instance, is an RNA virus whereas herpesvirus, which encompasses HCMV, is a DNA virus. A person skilled in the art thus recognizes that at least these known viruses are distinct in terms of structure and function and would not expect, or be able to predict, that a single agent would treat them all. Viruses, like cancers, are distinct and therefore there similarly is no “silver bullet” which treats them all.
As per prevention, there is no agent known to prevent viral infection generally.
The Level of One of Ordinary Skill
The level of skill in the art is high. The artisan using the claimed invention would be a person with medical training such as a medical doctor or physician with an MD degree or the equivalent. 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).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Amount of guidance/working examples
Applicant has demonstrated that the claimed compounds have activity against breast cancer cells (e.g. see Figures 1-8, growth inhibition curves of MCF7 cells) which indicates that invention may have use in treating breast cancer. However, no experimental or other data is provided to show the instant compounds treat any other cancer embraced by the claims. Moreover, no evidence is provided to suggest that MCF7 cells (breast cancer cells) are a model for any other form of cancer, nor is evidence provided to show that SIRT2 inhibitors are recognized as treating all forms of cancer generally.
Applicant has further demonstrated that the claimed compounds have activity against HCMV (pages 56-57); however, no other evidence is provided to show that the claimed compounds treat any other form of virus. The example provided with regard to coronavirus is prophetic (see page 57, to assess their antiviral activity, some compound will be tested). There is no evidence of the record to suggest these compounds also treat coronavirus which, as noted in the state of the art, is distinct from HCMV. Moreover, there is no evidence that the claimed method prevents viral infection. It is presumed “prevention” of the claimed viral infection would require a method of identifying those individuals who will become infected before they exhibit symptoms. There is no evidence of record that would guide the skilled clinician to identify those who have the potential of becoming afflicted. Nothing in the specification teaches how one skilled in the art identifies a subject who’s disease will be prevented. Applicant’s evidence does indicate any viral infection is prevented in a subject as is claimed.
The specification does not provide any guidance to one of ordinary skill in the art to extrapolate the in vitro data provided by Applicant to the treatment of all types of distinct forms of cancer or viral infections embraced by the claims. 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)."
That conclusion is clearly justified here and one skilled in the art could not practice the full scope of the claimed invention without undue and unreasonable experimentation.
Claim Rejections - 35 USC § 112b
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-15 and 17-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. [A] claim is indefinite when the boundaries of the protected subject matter are not clearly delineated and the scope is unclear (MPEP 2173.04). The following terms and/or phrases render the scope of the claims unclear because the specification does not provide a scope limiting definition of the phrase or term, or any direction for ascertaining the scope of the limitation indicated by the term or phrase. Accordingly, one skilled in the art could not ascertain the metes and bounds of the claimed invention.
Claim 1 is drawn to a composition; however, the claim only requires a compound of Formula I. A composition requires a carrier. Presently, the claims are only drawn to a compound as this is the only required structural limitation. The claim is indefinite because it is not clear if Applicant intends to claim a composition comprising Formula I or just the compound. If Applicant intends a composition, then Examiner recommends amending the claim to require a carrier. Otherwise, claim 1 should recite “A compound of Formula I”.
Claim 1 further recites wherein R1 or R2 is
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. This structure renders the scope of the claims unclear because there is no indication regarding how the group is attached to Formula I and it is further unclear if this group requires a -CH3 as a person skilled in the art would understand that the end of a bond (indicated below) implies a methyl group. Appropriate clarification is required.
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Claim 1 teaches R3 and R4 are aryl, cycloalkyl or cycloalkoxy wherein each aryl, cycloalkyl or cycloalkoxy may have 0 to 3 heteroatoms. This limitation is confusing because aryl or cycloalkyl with at least 1 heteroatom would be heteroaryl or heterocyclyl and no longer aryl as defined in the specification (aryl is defined in the specification as C6-C14 aromatic moiety, see page 25). A definition in the specification which distorts the meaning of an accepted term renders the claims confusing (In re Hill 73 USPQ 482). Moreover, cycloalkoxy, which is not defined in the specification, would be understood to be a heterocycloalkyl ring with an O atom (e.g. tetrahydropyran). Accordingly, cycloalkoxy having 0 heteroatoms is also confusing. The claim is indefinite because it is not clear if Applicant intends to claim that R3 and R4 can be heteroaryl and heterocyclyl. Appropriate clarification is required.
Claim 1 further recites when “R3 and R4 are aryl, said aryl is not substituted…”. The limitation “aryl” is indefinite at this occurrence because it is not clear if by “aryl” Applicant also intends heteroaryl and heterocyclyl. Appropriate clarification is required.
Claims 2-15 and 17-19 depend directly or indirectly from claim 1, do not cure all of the above deficiencies, and are therefore also indefinite.
Claim 8 recites “wherein the composition is selected from..”; however, the claim recites compounds of Formula I. Formula I itself is not a composition. The claim would be more clear if amended, for instance, to recite “wherein the compound of Formula I is selected from…”.
Claim 14 recites “The composition of claim 13, selected from the group consisting of” and then the claim displays compounds of Formula I. The claim is somewhat unclear because Formula I is not a composition. Formula I is a compound. The claim would be more clear if amended to recite, for example, “The composition of claim 13, wherein the compound of Formula I is selected from the group consisting of”.
Claim 17 recites “cancer” which is indefinite because the scope of “cancer” has not been defined by the specification. Cancer is a generic term that corresponds to thousands of distinct diseases, and based on the specification, one skilled in the art could not say which cancers are included in the scope of the claim. Examiner suggests amending the claim to recite specific cancers for which Applicant has support.
Claim 19 recites “viral infection” which is indefinite because the scope of “viral infection” has not been defined by the specification. The specification provides some examples of viruses; however, there are more than 3600 species of virus known and so it is not clear which viral infections are intended to be included in the scope of the claim. Examiner suggests amending the claim to recite specific viral infections for which Applicant has support in the specification.
Claim 14 is indefinite for reciting improper Markush language. The final line of the claim recites “and a pharmaceutically acceptable salt”; however, the claim should recite “
Allowable Subject Matter
Claim 1 would be allowable if rewritten or amended to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action.
Claims 2-15 and 18 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: The closest reference to the instant claims is Remiszewski et al. (WO2016/077232 A2) (hereinafter “Remiszewski”). Remiszewski teaches generic compounds of Formula I including example 7 (page 28, pictured below for convenience). The difference between Remiszewski and the instant claims is that the instant claims require that one of R1 or R2 is a ureido group corresponding to
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. Remiszewski does not teach wherein R1 or R2 is a ureido group as required by the claims. There is no teaching which would have motivated one of ordinary skill in the art prior to the effective filing date of the claimed invention to specifically modify Remiszewski into the claimed invention with any reasonable expectation of success.
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Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEVIN MARTIN whose telephone number is (571)270-0917. The examiner can normally be reached Monday - Friday 8 am - 5 pm.
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December 30, 2025
/K.S.M./Examiner, Art Unit 1624
/BRUCK KIFLE/Primary Examiner, Art Unit 1624