CTNF 18/006,688 CTNF 98186 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia 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 present Application, filed January 23, 2024, is a national stage entry under 35 U.S.C. § 371 of International Patent Application No. PCT/US2021/071037, filed July 28, 2021, which claims the benefit of U.S. Provisional Patent Application No. 63/057,402, filed July 28, 2020. Status of the Claims In the amendment filed January 24, 2023, claim 6 is amended. Claims 1-20 are currently pending. Information Disclosure Statement The information disclosure statement (IDS) submitted on June 22, 2023 is acknowledged. Claim Rejections - 35 USC § 112 07-30-02 AIA 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 1–5, 12, 14, and 18–19 are indefinite : 07-34-01 Claims 1–5, 12, 14, and 18–19 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. Claims 1 and 14 are indefinite for reciting “a therapeutic agent that results in dissociation of hexokinase 1 (HK1) from the outer membrane of mitochondria and into the cytosol of macrophage cells in the subject”, because a person of ordinary skill in the art could not reasonably determine the metes and bounds of this limitation. The agent is defined solely by its ultimate biological effect on the subcellular localization of HK1, with no structural, mechanistic, or class constraint, and no specified potency or specificity of effect, nor of an assay to determine the effect, by which one could determine whether any given compound satisfies the definition. As such, one could not reasonably determine the scope of compounds that fit the recited definition. Claims 2–5 are indefinite for depending from claim 1 without curing this indefiniteness, and claim 15 is indefinite for depending from claim 14 without curing this indefiniteness. For the purpose of examination against the prior art, an agent of claim 1 will be understood as an agent that has been described as being capable, or shown to be capable, of causing dissociation of HK1 from the mitochondrial membrane. Similarly, claims 12 and 18 are indefinite for reciting “a therapeutic agent that inhibits the activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH).” As above, the claim recites no threshold of potency or specificity of effect, nor even mechanism of “inhibition.” For example, it would be unclear whether a compound that modulates a distal upstream process which then has a cascading inhibitory effect on GAPDH activity, among many other effects, would be an agent of claim 12. Furthermore, it would not be clear what constitutes “the activity” of GAPDH, because GAPDH is known to have a number of activities, including catalysis of glycolytic oxidation/phosphorylation of glyceraldehyde-3-phosphate (the canonical activity); microtubule binding and membrane fusion/trafficking; binding to voltage-dependent anion channel in mitochondria, promoting apoptosis; and various nuclear functions following nuclear S-nitrosylation-induced nuclear translocation, such as uracil DNA glycosylation and one or more signalling cascades that lead to cellular dysfunction and death. See, for example, the non-patent publication, The diverse functions of GAPDH: views from different subcellular compartments , Cellular Signalling , 23 , pgs. 317-323 (2011) by Tristan et al. It therefore would be unclear whether inhibiting “the activity” of GAPDH requires inhibiting any one of the several known GAPDH activities, some unstated subset of them, or something else. Further to this point, it is noted that different examples of agents of claim 12 (such as those of claim 13) appear to mainly effect different activities of GAPDH, and in particular, it is unclear what activity dihydromanumycin A inhibits or what the basis is for regarding it an inhibitor of GAPDH. Claim 19 is indefinite for depending from claim 18 without curing this indefiniteness. For the purpose of examination against the prior art, an agent of claim 12 or 18 will be understood as one that has been described as being capable, or shown to be capable, of directly or indirectly causing an attenuation of some activity of GAPDH. Notes on claim interpretation : Regarding the element of claim 8 wherein the effective amount of clotrimazole induces elevated production of IL-1β, TNFα, and IL-6 by the macrophage cells, this is an intended result that cannot be given patentable weight in this instance. “ A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited. ” Minton v. Nat'l Ass'n. of Sec. Dealers , 336 F.3d 1373, 1381 (Fed. Cir. 2003 – emphasis added to quotation). See also MPEP § 2111.04(I), which makes clear that this rule of claim construction is not limited to clauses marked off by the term “whereby,” but is applicable to functionally equivalent clauses having terms such as “wherein” or other functionally equivalent terms. As such, any prior art methods teachings method steps indistinguishable from those of instant claim 1 will be understood to produce the same product. The wherein clauses of claims 9-11 are deemed to be mere intended results and do not carry patentable weight for the same reason. Claims 8–11 each depend from claim 7 and recite wherein clauses stating that the effective amount of clotrimazole produces a specified biological result. These clauses are treated as intended results that are not given patentable weight, because they simply express hoped-for outcomes of the positively recited administering step without further limiting the manner in which the method is performed. Minton v. Nat’l Ass’n of Sec. Dealers, 336 F.3d 1373, 1381 (Fed. Cir. 2003); MPEP § 2111.04(I). The method claim preambles are construed as limiting the claims to the extent that they define or limit the patient population. Thus, the preamble of claim 1 limits the method of treatment to subjects having an immunodeficiency disease or disorder. Similarly, the preamble of claim 14 limits the method of treatment to subjects who are in need of, or would benefit from, elevating production of one or more inflammatory cytokines. The patient population of claim 14 includes the includes the patient population of claim 1, and is likely somewhat larger. Claim 14 is not understood to require that any actual elevation in inflammatory cytokines occur or be measured, any more than claim 1 is construed to require any particular clinical outcome. The two claims are thus largely identical except that claim 14 includes a somewhat larger patient population than does claim 1. The same analysis is applied to claims 12 and 18, which differ from claims 1 and 14, respectively, in that a GAPDH inhibitor is administered rather than an agent that can dissociate HK1 from the mitochondrial membrane. Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-23-aia AIA 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. Claims 1–2, 6–12, and 14-19 are obvious over Sen : 07-21-aia AIA Claim s 1–2, 6–12, and 14-19 are rejected under 35 U.S.C. § 103 as being unpatentable over the non-patent publication, Role of Hexokinase-1 in the survival of HIV-1-infected macrophages , Cell Cycle , 14 , pgs. 980–989 (2015) by Sen et al. (hereinafter “ Sen ”) . Claim 1 recites a method of treating an immunodeficiency disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a therapeutic agent that results in dissociation of hexokinase 1 (HK-1 or HK1) from the outer membrane of mitochondria and into the cytosol of macrophage cells in the subject. Sen teaches a study of the role of HK-1 in HIV-1-infected macrophages (i.e. an immunodeficiency disease; Abstract). Sen teaches that HK-1 plays a non-metabolic role in HIV-1 infected macrophages by binding to mitochondria thereby maintaining mitochondrial integrity, but that treatment with clotrimazole induces dissociation of HK-1 from mitochondria resulting in membrane depolarization and caspase-3/7 mediated apoptosis (Abstract). Sen further teaches that long-lived infected macrophages can serve as reservoirs for HIV-1 persistence in the brain and promote inflammation in the CNS of patients receiving combination antiretroviral therapy (Introduction, first paragraph). On this basis, Sen suggests that targeting the HK-1/mitochondrial membrane interaction to induce apoptosis in infected macrophages may be beneficial in purging the HIV reservoir that persistently infected macrophages typically represent (Abstract). Sen thus teaches that clotrimazole is an agent that can dissociate HK-1 from the outer membrane of mitochondria and into the cytosol of HIV-1 infected macrophages, and suggests this illustrates a beneficial therapeutic approach for treating HIV-1. It is therefore arguably directly suggested, but would have been at least obvious in view of the teachings of Sen , to administer an effective amount of a therapeutic agent, such as clotrimazole, that results in dissociation of HK-1 from the outer membrane of mitochondria in the cytosol of macrophage cells to a subject harboring an HIV-1 infection (and immunodeficiency disease) in order to treat the immunodeficiency disease. Claim 1 is therefore obvious over Sen . Because, as noted above, claim 14 differs from claim 1 only in the patient population, and includes the patient population of claim 1 (subjects having an immunodeficiency disease or disorder), claim 14 is obvious for the same reasons as is claim 1. With respect to claim 2, Sen teaches the immunodeficiency disease or disorder is HIV-1 (HIV infection). With respect to claims 6-7, Sen teaches the example of clotrimazole as the therapeutic agent that causes dissociation of HK-1 from the outer membrane of mitochondria and into the cytosol of HIV-1 infected macrophage (Abstract). As noted above, claims 8-11 recite mere intended results and are therefore not patentably distinct from their base claim, claim 7. Claims 8-11 are therefore obvious over Sen for the same reasons as is claim 7. Claim 12 recites a method of treating an immunodeficiency disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a therapeutic agent that inhibits the activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Claim 12 is thus similar to claim 1, except that claim 12 recites administering an agent that can attenuate an activity of GAPDH, rather than an agent that can dissociate HK1 from the mitochondrial membrane in a macrophage. Sen is applied to claim 12 as to claim 1, above, and renders obvious a method of treating a subject with an immunodeficiency disease comprising administering clotrimazole to the subject. Moreover, and with respect to claim 18, clotrimazole is a therapeutic agent that inhibits the activity of GAPDH. See, for example, the non-patent publication, Hexokinase 1 cellular localization regulates the metabolic fate of glucose , Mol. Cell , 82 , pgs. 1261-1277 (2022) by De Jesus et al. (hereinafter, “ De Jesus ”) which teaches that treatment of RAW264.7 cells with clotrimazole caused a significant decrease in GAPDH activity (pg. 1269, paragraph spanning the bottom of the left column to the top of the right column). Note that De Jesus is cited not as prior art, but merely to support the contention that clotrimazole is an agent capable of inhibiting GAPDH activity within the scope of claim 12. Given this, Sen thus renders claim 12 obvious for the same reasons as Sen renders claim 1 obvious. Claim 18 is to claim 14 as claim 12 is to claim 1. That is, claim 18 differs from claim 12 only in the patient population, and includes the patient population of claim 14 (subjects having an immunodeficiency disease or disorder). Thus, claim 18 is obvious for the same reasons as is claim 14. With respect to claims 15 and 19, as noted above, these claims recite intended results that do not patentably distinguish them from their base claims 14 and 18, respectively. As such, claims 15 and 19 are obvious for the same reasons as are claims 14 and 18. With respect to claims 16-17, as noted with respect to claims 6-7, Sen teaches that the agent capable of dissociating HK-1 from the mitochondrial membrane is clotrimazole . Allowable Subject Matter 12-151-08 AIA 07-43 12-51-08 Claim s 13 and 20 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER K SHOWALTER whose telephone number is (571)270-0610. The examiner can normally be reached M-F 9:00 am to 5:00 pm, eastern time. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629 /JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629 Application/Control Number: 18/006,688 Page 2 Art Unit: 1629 Application/Control Number: 18/006,688 Page 3 Art Unit: 1629 Application/Control Number: 18/006,688 Page 4 Art Unit: 1629 Application/Control Number: 18/006,688 Page 5 Art Unit: 1629 Application/Control Number: 18/006,688 Page 6 Art Unit: 1629 Application/Control Number: 18/006,688 Page 7 Art Unit: 1629
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