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 .
Status of claims
Pending claims 1-2, 4-5, 9, 11, 13, 15, 17-18, 20-21, 24-26, 30-33, and 38 have been examined on the merits.
Claim Rejections - 35 USC § 112 (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 33 and 38 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first
paragraph, as failing to comply with the enablement requirement. The claims contain subject
matter which was not described in the specification in such a way as to enable one skilled in the
art to which it pertains, or with which it is most nearly connected, to use the invention.
The specification does not reasonably provide enablement for treating a disease, disorder or condition by inhibiting Bcl2-associated X protein (BAX) and/or Bcl-2 antagonist killer (BAK), wherein the disease or disorder is a neuronal damage associated with ischemia, chemotherapy-induced cardiomyopathy, and donor HSPC death. Furthermore, the specification does not enable any person skilled in the art (POSITA) to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The how to use requirement of the enablement statute, when applied to a method claim, refers to operability and how to make the claimed method work "The factors to be considered (in making an enablement rejection) have been summarized as the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims", In re Rainer 146 USPQ 218 (1965); In re Colianni, 195 USPQ 150, Ex parte Formal, 230USPQ 546. The specification provides in vitro mechanistic data demonstrating that the claimed compounds inhibit BAX/BAK mediated cell death in an actinomycin-D treated BMK cell. However, the specification fails to provide disease-specific in vivo evidence demonstrating that administration of the claimed compounds successfully treats neuronal damage associated with ischemia, chemotherapy-induced cardiomyopathy, and donor HSPC death.
The instant claims encompass method for treating a disease, disorder or condition by inhibiting Bcl2-associated X protein (BAX) and/or Bcl-2 antagonist killer (BAK), wherein the disease or disorder is a neurodegenerative disease, ischemia or cardiomyopathy. The claimed method involves fundamentally different biological system that are not comparable or overlap between neuronal ischemic injury, chemotherapy-induced cardiomyopathy and donor HSPC death. Although apoptosis mediated by BAX/BAK may contribute to each condition, apoptosis represents only one component of the multifactorial disease process. Thus, a POSIAT would recognize that the breadth of the claims extends far beyond simply demonstrating inhibition of BAX or BAK. And yet, the specification provides only biochemical and cell-based assay demonstrating that certain compounds bind to BAX or inhibit BAX/BAK function in mitochondria, as an example. However, the specification does not demonstrate that administration of the claimed compounds at an effective dose successfully treats each of the distinct pathological diseases encompassed by the claims. The specification also fails to disclose recognized disease-specific efficacy studies evaluating any improvement in clinically relevant endpoints such as neurological recovery, as an example. Consequently, practicing the full scope of the claimed methods would require undue experimentation. Thus, the specification fails to provide sufficient guidance or representative data, to enable a POSITA to reasonably predict which claimed compounds would be effective for each of the mechanistically distinct diseases, as recited in the instant claims without engaging in extensive trial-and-error experimentation.
The direction concerning treating these diseases found in the specification merely states Applicants' intention to do so. For example, the instant claims require that administration of the claimed compounds successfully treat neuronal damage associated with ischemia, chemotherapy-induced cardiomyopathy, and donor HSPC death. However, the specification provides little guidance demonstrating that administration of the representative compounds produces the claimed therapeutic or prophylactic outcomes. For example, the specification primarily demonstrates that certain compounds possess biochemical activity against the intended targets. However, inhibitions of BAX or BAK directly or indirectly mediated pathway, does establish that administration of the claimed compounds will successfully treat neuronal ischemic injury, chemotherapy-induced cardiomyopathy and donor HSPC death; thus, simply inhibiting BAX and/or BAK in vitro does not establish therapeutic efficacy. Although the assays establish that the compounds interact with the intended molecular target, however, inhibiting BAK and/or BAX does not alone does not establish therapeutic efficacy in patients suffering from heart failure or the claimed cardiovascular diseases. The distinction between target engagement and therapeutic efficacy is recognized throughout cardiovascular drug development. It is important to note that numerous lead compounds have demonstrated promising in vitro pharmacology, yet ultimately failed to demonstrate clinical benefit. Furthermore, because the nature of the invention involves systemic modulation of a signaling pathway essential for apoptosis regulation, substantial in vivo experimentation would be required to determine safe dosing regimens that avoids dysregulated apoptotic effects in other cellular systems, that could potentially cause a surge in autoimmune manifestations, or related pathology (see Mason et.,). The specification provides no such guidance. (Mason et al., Proc Natl Acad Sci USA. 2013 Feb 12;110(7):2599-604.)
The state of the prior art strongly supports a conclusion that the claimed therapeutic methods were not established or predictable at the time of filing. Although prior art established that BAK and BAX play central function as regulators of intrinsic apoptotic pathway and that excessive apoptosis is associated with numerous pathological condition such as neuronal injury, cardiac injury, and stem cell death. The prior art, as disclosed by Spitz, lack of any clinical evidence demonstrating BAX/BAK inhibitors are effective at treating the claimed diseases. For instance, Spitz (page 209) discloses that while multiple small molecules, peptides, and antibodies have been developed to modulate BAX at trigger, canonical, and non-canonical sites, these agents are structurally and mechanistically distinct from the claimed compounds, and yet none of them have been moved to clinical stage as methods of treatment. Currently, there are no direct BAX and/or BAK inhibitors in human clinical trials to treat the claimed diseases or disorders. Thus, a POSITA, considering the state of the art, would not reasonably expect that successful inhibition of BAK and/or BAK in biochemical assay or cell culture would necessarily translate into therapeutic benefits for patients in need thereof. (See Spitz et al., Trends Pharmacol. Sci. 2022 Mar; 43(3):206-220.)
The nature of the invention is clinical treatment of diseases by inhibiting BAX and/or BAK in neuronal ischemic injury, chemotherapy-induced cardiomyopathy and donor HSPC death, which involves physiological activity.
The predictability of the art clearly indicates that the specification lacks enablement, because the specification does indicate that inhibition of apoptosis alone is sufficient to produce therapeutic benefit across each of the clinically distinct diseases. For example, numerous therapeutic strategies directed toward reducing apoptosis, but there is no evidence that such approach results to therapeutic benefits such as neuroprotection or protection of ischemic myocardium (see Spitz et.,). Thus, these agents are limited to preclinical models and have not yet progressed to clinical trials or FDA approvals. Furthermore, there are no preclinical models demonstrating meaningful and clinical benefits of targeting BAX and/or BAK in a subject in need thereof. In addition, Masson (page 2599-2602) demonstrates that profound reduction or loss of BAK/BAX function leads to severe systemic or organ-specific autoimmune disease. Thus, prolonged or systemic inhibition of BAX/BAK, as contemplated by the claimed invention, presents substantial risk of disrupting physiologic apoptosis required for autoimmune tolerance, as an example. Thus, the specification does not provide in vivo data demonstrating that the claimed compounds can be administered at an effective and safe dose that achieve the desired inhibition of BAK/BAX-mediated cell death, while avoiding induction of autoimmune manifestation or other pathology associated with impaired intrinsic apoptosis. Thus, a POSITA would recognize that substantial, non-routine experiment would be required to validate targeting BAK/BAX as a clinical effective approach against neuronal damage associated with ischemia, chemotherapy-induced cardiomyopathy, and donor HSPC death. Thus, the specification does not provide sufficient guidance to determine effective dosing regimens or proper disease models, or patient population to avoid autoimmune complication. Thus, the specification fails to enable the full scope of the claimed methods of treating disease by inhibiting BAX and/or BAK.
(See Spitz et al., Trends Pharmacol Sci. 2022 Mar; 43(3):206-220; Mason et al., Proc. Natl. Acad. Sci. USA. 2013 Feb 12;110(7):2599-604).
The artisan using Applicant’s invention would be a physician with a MD degree and several years of experience.
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, 427 F.2d 833,839, 166 USPQ 18, 24 (CCPA 1970). Consistent with this principle, multiple small molecules, peptides, and antibodies, promising preclinical activity have failed to consistently translate into clinical efficacy, illustrating the unpredictability of developing therapeutically effective against neuronal injury, cardiac injury, and stem cell death. For example, Luna-Vargas (page 1-8 and 20) discloses that majority of pharmacological modulation of the intrinsic apoptotic pathway is largely directed towards inhibition of anti-apoptotic BCL-2 family members, rather than direct inhibition of the pro-apoptotic effector protein BAX or BAK. Luna-Vargas (page 1-8 and 20) also discloses 21 compounds targeting BCL-2 family, but few of them progressed into Phase I, II, and III clinical trials. In contrast, only a single direct BAX-targeting small molecule (BAM7) had been reported, and that compound remained in the preclinical stage. Luna-Vargas (page 1-8 and 20) discloses no known BAK-targeting small molecules had advanced into clinical development. This is consistent with Spitz’s disclosure demonstrating that multiple small molecules, peptides, and antibodies have been developed to modulate BAX, and yet none has been moved to clinical stage. Thus, despite intensive research into apoptosis, the art had not successfully translated direct pharmacological inhibition of BAK and/or BAX into clinical testing or approved as a therapeutic regimen. This supports a finding of great unpredictability in this field of endeavor (See Luna-Vargas et al., Trends Cell Biol. 2016 Dec;26(12):906-917; Spitz et al., Trends Pharmacol Sci. 2022 Mar;43(3):206-220.)
The breadth of the claims involves all of the thousands of compounds as well as BAK-BAX associated disease, including neuronal injury, cardiac injury, and stem cell death. It is noted that independent claim 33 does not specify to whom or what the effective amount of the compounds of claim 1 are administered. Additionally, the Examiner notes that the specification defines subject in paragraph [0041] of the specification to include all members of the animal kingdom. Therefore, the rejected claims are understood to be very broad with respect to the patient population (e.g., animals or cell lines). Although the specification provides sufficient information to synthesize the claimed compounds, and even disclosed the claimed compounds capable of reducing apoptosis; however, there is no evidence whether administration of such compounds actually treats the diseases recited in the instant claims. For example, treatment of neuronal damage associated with ischemia would require a model showing neuronal efficacy, blood-brain-barrier penetration, neurological recovery, and inhibition of apoptosis in neuronal tissues, however, none of which are disclosed in the specification. Furthermore, treating chemotherapy-induced cardiomyopathy or preserving donor HSPCs would require disease-specific cardiac-toxicity and transplantation models to demonstrate that apoptosis inhibition improves ventricular function, cardiac remodeling, or stem-cell engraftment. The specification, however, provides no evidence demonstrating any of these outcomes. The absence of such data clearly indicates a lack of enablement, as the prior art does not show that targeting BAX or BAK effectively treats the claimed diseases. Therefore, a novel therapeutic strategy of this type must include sufficient and reasonable information to allow a POSITA to understand how the treatment can be applied in practice. As mentioned above, while multiple small molecules, peptides, and antibodies have been developed to modulate BAX at trigger, canonical, and non-canonical sites, these agents are structurally and mechanistically distinct from the claimed compounds, and yet none has been moved to clinical stage. (See Spitz et al., Trends Pharmacol Sci. 2022 Mar;43(3):206-220.)
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries 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 1-2, 4-5, 9, 13, 15, 17-18, 20-21, 24-26, and 30-32, are rejected under 35 U.S.C. 103 as being unpatentable over Fakhoury et al., US 7,772,243, Dick et al., Pharm (Basel). 2020 Feb. 28; 13(3):36, Vacondio et al. Bioorg Med. Chem. Lett. 2013 Oct. 1; 23(19):5290-4.
Regarding claims 1-2, 4-5, 9, 13, 15, 18, 20, 24-26, and 32, Fakhoury (page 44) discloses pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein R2 is methoxy; R3 is hydrogen; L is propene; A is piperidine; R1 is Cl and Fluorine with n =2; m =3. Fakhoury, however, discloses
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the core structure is quinazoline instead of isoquinoline, containing an extra nitrogen atom. Dick (page 2) teaches –CH= and –N= are classical bioisosteres, specifically identifying aromatic ring equivalent such as benzene and pyridine, as an example for such substitution.
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Therefore, this disclosure would have informed a person of ordinary skill in the art (POSITA) that such substitution is a routine structural modification expected to preserve similar steric and electronic characteristics in the search of a lead compound. Furthermore, a POSITA would have found it obvious to replace the -N= atom in the pyrimidine portion of the quinazoline core with a -CH= group, thereby arriving at the corresponding isoquinoline scaffold as a predictable classical bioisosteric analogue.
Regarding claims 17, 21 and 30, and as applied above to 1-2, 4-5, 9, 13, 15, 18, 20, 24-26, and 32 above, Fakhoury does not explicitly teach L linker is alkylene or the absence of R2 substituent.
Regarding L is an alkylene, Fakhoury does not explicitly teach L is an alkylene. However, Vacondio (page 5290-5291, Table 1; emphasis added) teaches closely related compounds (i.e., compound 5) having the same core scaffold but with the corresponding saturated alkane linker. It also important to note, Vacondio (page 5290-5291, Table 1) explicitly discloses that L linker as either saturated or unsaturated. Therefore, the existence of both saturated and unsaturated linker variants in the prior art demonstrates that each was recognized as a variable linker for the same or closely related chemical scaffold. Therefore, a POSITA would have recognized the alkene and alkane linkers to represent alternative structural variants and would have found it obvious to substitute one for another in the search of leads compounds. Thus, such substitution would have also recognized by a POSITA as routine optimization by exploring structurally related linker analogues. Therefore, it would have been obvious to a POSITA to modify Fakhoury’s teachings in view of Dick and Vacondia and arrive at the claimed compounds, (i.e., compound 1, as example), because the combined teachings of Fakhoury, Dick and Vacondia teach comparable compounds as claimed in the instant application.
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Furthermore, regarding the absence of R2 substituent, Fakhoury teaches compounds in which isoquinoline scaffold bears an R2 substituent, however, does not teach compounds lacking the R2 substituent. Vacondia (page 5290-5291, emphasis added), however, teaches comparable compounds encompassing both the presence and absence of the R2 substituent on the isoquinoline scaffold. This then indicates that substituted and unsubstituted isoquinoline cores were recognized in the art as alternative structural variants. Therefore, based on this disclosure, it would have been obvious to a POSITA to modify Fakhoury’s teachings to omit the R2 substituent and arrive at the corresponding unsubstituted analogue, which represent a routine variation to optimize and evaluate structural related compounds to identify suitable lead compounds. Therefore, the presence or absence of the R2 substituent merely represent a predictable selection of a known alternative disclosed in the art and to arrive at the claimed compound.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES H ALSTRUM-ACEVEDO can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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