NON-FINAL REJECTION
This application is a 35 U.S.C. 371 (national stage) application of PCT/JP2023/015870, filed Apr. 21, 2023, which claims benefit of foreign priority to JP 2022-070667, filed Apr. 22, 2022.
Claims 1-16, as amended, are pending.
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
Acknowledgment is made of applicant's claim to foreign priority under 35 U.S.C. 119(a)-(d).
Information Disclosure Statement
The information disclosure statements (IDS) submitted on Nov. 13, 2024 (2) and Mar. 20, 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Rejections - 35 U.S.C. § 112(b) - Indefiniteness
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.
1. Claims 1-16 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.
The claims are drawn to compounds of formula (1), a pharmaceutically acceptable salt thereof, or a prodrug of the compound or the salt, having the structural formula,
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.
The instant specification provides that "[e]xamples of the prodrug of the above compound can include phosphate prodrugs, more specifically, a compound in which R1 is —CH2—O—PO3H2, and a compound in which at least one of the nitrogen atoms as ring member atoms of A is substituted with —CH2—O—PO3H2" (para. [0035]). However, the term "prodrug" is otherwise undefined.
While prodrugs are understood in the art as compounds which are therapeutically inactive until administered and metabolized to its active form, the term "prodrug" encompasses a genus of modified compounds defined in purely functional terms, which sets no limit on the moieties or functional groups which may be added to any position of the claimed compounds to yield a “prodrug” thereof.
As recognized by MPEP § 2173.05(g), a claim term is merely functional descriptive language when it recites a feature "by what it does rather than by what it is" (e.g., as evidenced by its specific structure). In re Swinehart, 439 F.2d 210, 212, 169 USPQ 226, 229 (CCPA 1971).
Here, the term "prodrug" ambiguously defines the claimed compounds by their function, rather than by structure. Thus, the scope of the compounds encompassed by the term “prodrug,” and the nature of the steps required to prepare them, have no clear boundary. What might constitute a “prodrug” of a compound of formula (1) or a salt thereof is vague and open to interpretation. Therefore, one of ordinary skill in the art could not clearly distinguish compounds which are included by the claims, from compounds which are excluded.
Because a skilled artisan would not be reasonably apprised of the scope of the claimed invention, infringing compounds cannot be distinguished from non-infringing compounds, rendering the metes and bounds of the claims indefinite.
2. Claims 14 is 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.
Claim 14 is drawn to a method for activating aldehyde dehydrogenase 2 (ALDH2), comprising administering an effective amount of the compound of formula (1), a pharmaceutically acceptable salt of the compound, or prodrug of the compound or the salt, to a patient in need thereof.
However, the specification fails to define "a patient in need of aldehyde dehydrogenase 2 activation," a patient population which has no commonly understood and accepted meaning in the art. Thus, claim 14 amounts to a method of treating an unspecified disease or condition, leaving the patient population encompassed by the claim open-ended and undefined.
Certain diseases or conditions associated with ALDH2 activity are disclosed in the specification (para. [0042]): Fanconi's anemia, osteoporosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease, pancreatitis, ischemia-reperfusion injury, peripheral arterial disease, Alzheimer's disease, Parkinson's disease, esophageal cancer, head and neck cancer, pain, and diabetic retinopathy, as recited by claim 16.
However, "a patient in need of aldehyde dehydrogenase 2 activation" is a broader term, encompassing an ambiguous patient population having unrelated disorders with widely varying etiologies. This generic, open-ended terminology does not set forth the metes and bounds of the claims with sufficient clarity. Because infringing activity cannot be clearly distinguished from non-infringing activity, the metes and bounds of the claims are indefinite.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
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 and 16 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 acute pain, does not reasonably provide enablement for (1) treating Fanconi's anemia, osteoporosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease, pancreatitis, ischemia-reperfusion injury, peripheral arterial disease, Alzheimer's disease, Parkinson's disease, esophageal cancer, head and neck cancer, or diabetic retinopathy; or for (2) preventing any disease or condition. The specification does not enable one of ordinary skill in the art to practice the invention commensurate in scope with the claims.
MPEP § 2164.01(a), citing In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), sets out the factors to consider whether experimentation is undue, which are addressed below.
(A) The breadth of the claims.
Claim 14 is drawn to a method of activating aldehyde dehydrogenase 2 (ALDH2) in a patient in need thereof, comprising administering an effective amount of a compound of formula (1).
Claim 16 is drawn to a method of treating and/or preventing Fanconi's anemia, osteoporosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease, pancreatitis, ischemia-reperfusion injury, peripheral arterial disease, Alzheimer's disease, Parkinson's disease, esophageal cancer, head and neck cancer, pain, and diabetic retinopathy, comprising administering an effective amount of a compound of formula (1).
Thus, the claims encompass both treating (after disease onset) and preventing (prophylactic administration prior to disease onset) a vast and diverse range of diseases and conditions, supported by only one in vivo example in the specification.
(B) The nature of the invention. The invention relates to the narrow genus of compounds of formula (1), their activity as ALDH2 activators, and their use in methods of treating and/or preventing diseases and conditions via ALDH2 activation.
(C) The level of predictability in the art. The background art cited in the specification (paras. [0002]-[0012]) establishes general associations between ALDH2 activity and the claimed diseases and conditions, as well as other ALDH2 activators. However, the prior art does not establish a predictable correlation between in vitro ALDH2 activation by a specific compound class and in vivo therapeutic or prophylactic efficacy across these unrelated disease states. Translation from in vitro enzyme activation to clinical efficacy in living patients with complex, multi-factorial diseases remains highly unpredictable. The acute inflammatory pain model of Test Example 5 is not representative of the other claimed conditions, and does not reliably predict efficacy in treating or preventing unrelated chronic diseases.
Prevention is particularly unpredictable, as it connotes the absolute absence of a condition which cannot reasonably be achieved with regard to the claimed conditions, or in medicine generally. In addition, there is no definitive method by which to determine whether a patient will develop the claimed conditions in the future, and thus, be in need of preventive therapy. Even if a patient can be identified as having known risk factors for a disease, there is no way to predict that a patient will, in fact, later develop that disease. Further, the failure of a condition to develop cannot reliably be attributed to the active agent; for example, the condition may reverse or resolve due to other factors.
(D) The amount of direction provided by the inventor. The examples presented in the specification relate mainly to the synthesis of compounds of formula (1) (Examples 1-9); evidence that the claimed compounds function as ALDH2 activators in vitro (Test Examples 1-1 and 1-2); and their metabolic stability in mouse and human microsomes (Test Examples 2-4).
Only one in vivo working example is disclosed (Test Example 5), wherein carrageenan-induced pain in a mouse model is reduced by administering a compound of formula (1) (the compound of Example 3).
Thus, the disclosure is mainly directed to compounds of formula (1), their mechanism of action, and their behavior in vitro, rather than to methods of treating or preventing disease in vivo. The specification provides no specific guidance on dosing regimens, biomarkers, duration of treatment, or clinical endpoints for any disease other than pain; and no guidance whatsoever on preventative or prophylactic use for any condition. The single pain-treatment example does not reasonably correlate with or enable the breadth of claims 14 and 16.
(E) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Despite the narrowly drawn genus of compounds of formula (1) and a proposed mechanism of action, a demonstration that one compound of formula (1) (Example 3) treats one condition (acute pain), without more, is insufficient to enable methods of treating or preventing any disease mediated by aldehyde dehydrogenase 2, as recited by claim 14, or the laundry list of diseases and conditions recited by claim 16.
Therefore, in view of the unpredictability in the art, coupled with the breadth of the claims and a lack of guidance and direction provided by the instant disclosure, one of ordinary skill in the art could not practice the invention commensurate with the scope of the claims without undue experimentation.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12,509,423 in view of Pennington et al. (J. Med. Chem. 60, 3552−3579 (2017), cited on PTO-892).
Reference claims 1-14 are drawn to a compound of formula (1), a pharmaceutically acceptable salt of the compound, or a prodrug of the compound or the salt:
Reference Compounds
Examined Compounds
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wherein variable groups R1, R2, R3, and X1 are defined identically to formula (1) of the examined claims, and differing only slightly at L of examined formula (1), which is absent or alkylene; and at X2, which can be hydrogen as well as halogen.
Reference claim 15, like examined claim 14, is drawn to a method for activating aldehyde dehydrogenase 2, comprising administering an effective amount of the compound of formula (1), the pharmaceutically acceptable salt of the compound, or the prodrug of the compound or the salt to a patient in need thereof.
Reference claim 16, like examined claim 15, is drawn to a pharmaceutical composition comprising the compound of formula (1), the pharmaceutically acceptable salt of the compound, or the prodrug of the compound or the salt.
The reference compounds differ from the examined compounds in that the terminal ring of the reference compounds is phenyl, while the terminal ring of the examined compounds is pyridinyl (shown above, circled).
However, pyridinyl is a well-known replacement for phenyl which is commonly employed to improve a variety of pharmacological properties in multi-parameter optimization.
For example, Pennington and Moustakas (cited on PTO-892) disclose a high-impact design element termed “the necessary nitrogen atom,” wherein substitution of a CH group with a N atom in aromatic and heteroaromatic ring systems gives rise to substantial improvement
in a key pharmacological parameter (≥10-fold) (p. 3552, right col.). Traditionally regarded as a classical bioisosteric replacement, the substitution of a CH group with a N atom in aromatic and
heteroaromatic ring systems can have many important effects on molecular and physicochemical properties of relevance to multi-parameter optimization (para. bridging pp. 3552-3553).
Replacing a ring carbon with nitrogen introduces a strong hydrogen bond acceptor, increases polar surface area, decreases lipophilicity, and improves aqueous solubility (p. 3553, left col.). Many examples of dramatically improved properties upon replacing phenyl with pyridinyl are cited, including increased biochemical potency (Figs. 11, 12, 14, 15); cellular potency (Figs. 18, 20); target selectivity (Fig. 24); aqueous solubility (Figs. 30, 32); cellular permeability (Fig. 35); protein binding (Figs. 36, 39); metabolic stability (Figs. 40-42); CYP inhibition (Fig. 45); oral absorption (Fig. 59); and plasma clearance (Fig. 61).
Pennington and Moustakas conclude with a list of eleven factors to consider when choosing the best ring carbon to replace with nitrogen (p. 3573, right col.).
Therefore, it would have been predictable to one of ordinary skill in the art of medicinal chemistry as of the filing date to substitute phenyl with pyridine with a reasonable expectation of success, because Pennington and Moustakas teach that the replacement of a CH group with a N atom in aromatic and heteroaromatic ring systems can dramatically improve molecular and physicochemical properties that can translate to improved pharmacological profiles (abstract).
As recognized by MPEP § 2144.09, a prima facie case of obviousness may be made when chemical compounds have (1) very close structural similarities and (2) similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA E. TOWNSLEY whose telephone number is 571-270-7672. The examiner can normally be reached on Mon-Fri from 10:00 am to 6:00 pm (EST). If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jeff S. Lundgren, can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARA E. TOWNSLEY/Examiner, Art Unit 1629
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