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 .
Election/Restrictions
Applicant's election with traverse of the compound in the reply filed on 01/26/2026 is acknowledged. The traversal is on the ground(s) that the cited reference, WO 2005023815, does not teach or suggest the use of the elected compound as recited in the instant claims. This is not found persuasive because the election of species requirement is made on the basis that the genus of Formula I is not a special technical feature in view of the art.
The requirement is still deemed proper and is therefore made FINAL.
Priority
Examiner acknowledges that, according to the Filing receipt received 06/26/2024, that the instant application 18/546,234 filed 08/11/2023 is a 371 of PCT/NZ2022/050017 filed 02/11/2022 which claims benefit of U.S. provisional application 63/148,962 filed 02/12/2021.
Information Disclosure Statement
The Information Disclosure Statements filed on 08/11/2023 and 02/13/2025 are in compliance with the provisions of 37 CFR 1.97 and have been considered in full. A signed copy of list of references cited from the IDS is included with this Office Action.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see specification, p. 27 and 49). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 42 and 47 are objected to because of the following informalities:
C;
Claim 47: “any IGF Binding Protein”, “any statin”, and “any appetite suppressant” should read “an IGF Binding Protein”, “a statin”, and “an appetite suppressant” respectively.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 35-54 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 term “prodrug” renders claim 35 and dependent claims 36-54 indefinite as a prodrug does not have a defined structure known in the art. For example, one would not be apprised of the pharmacologically inactive form of the claimed compound from the simple recitation of “prodrug” as the compound itself has multiple sites to which a prodrug moiety could bind. Moreover, one could not ascertain as to which prodrug moieties are within the scope of the claim, resulting in millions of combinations. One could not possibly envisage all the possibilities of a prodrug of any compound of the instant invention.
Claim 47 recites the limitations “the hst/Kfgk gene product” and “the anti-MAdCAM-1 antibody MECA-367”. These limitations lack antecedent basis.
Claim 49 recites the limitation “the pharmaceutical composition”. This limitation lacks antecedent basis. Claim 49 depends upon claim 35 which does not encompass a pharmaceutical composition.
Claim 50 recites “to an including about 600 mg/kg”. The term “including” causes confusion as it suggests that other values not otherwise recited in the claim, outside of “about 0.001 mg/kg” to “about 600 mg/kg”, are within the scope of the claim.
Claim Rejections - 35 USC § 112(a)
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 35-54 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 administering a therapeutically effective amount of Formula I to alleviate symptoms of Prader-Willi Syndrome (claim 35), or reducing the likelihood or severity of one or more symptoms of Prader-Willi Syndrome (claim 44), does not reasonably provide enablement for administering a therapeutically effective amount of Formula I sufficient to prevent symptoms of Prader-Willi Syndrome or preventing one or more symptoms of Prader-Willi Syndrome. 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.
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)".
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The specification (p. 8) defines “therapeutically effective amount” to include amounts sufficient to prevent one or more symptoms of the disorder being treated. Claim 44 is further directed toward reducing the likelihood/severity or preventing one or more symptoms of Prader-Willi Syndrome.
It is presumed “prevention” of the claimed disease would require a method of identifying those individuals who will develop the claimed diseases 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 or what symptoms they will exhibit.
The factors to be considered in making an enablement rejection were summarized above. 1) As discussed above, preventing diseases and symptoms requires identifying those patients who will acquire the disease or symptom before the Prader-Willi syndrome occurs. This would require extensive and potentially opened ended clinical research on healthy subjects. 2) Page 8 of the specification defines “therapeutically effective amount” to include an amount sufficient for prevention. Claim 44 is additionally specifically directed toward prevention. 3) There is no working example of such a preventive procedure in man or animal in the specification. 4) The claims rejected are drawn to clinical pharmacology and are therefore physiological in nature. 5) The state of the art is that no general procedure is art-recognized for determining which patients generally will suffer from Prader-Willi syndrome, or symptoms thereof, before the fact. 6) The artisan using Applicants invention would be a Board-Certified physician in neurodevelopmental diseases with an MD degree. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of Prader-Willi syndrome and/or its symptoms. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. 7) 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). 8) The claims broadly read on all patients, not just those undergoing therapy for the claimed disorder.
Claim 46 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 the therapeutic agents as listed in claim 47, does not reasonably provide enablement for a therapeutic agent generally. 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.
The instant claims are drawn to a method of treating Prader-Willi Syndrome in a subject, comprising administering a compound of Formula I. The claims are further drawn to administering an additional “therapeutic agent”. The specification does not define that which is intended in the use of a “therapeutic agent”, thus the scope of the claims is incredibly broad and reads on thousands of substances. The majority of such substances are not contemplated by the instant disclosure. 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).
MPEP 2164.01(a) states, "A conclusion of lack of enablement means that, based on the evidence 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.
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 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.
Claim(s) 35-54 is/are rejected under 35 U.S.C. 103 as being unpatentable over Neuren Pharmaceuticals Limited (Annual Report 2018; hereinafter “Neuren”) in view of Heksch et al. (Translational Pediatrics; IDS filed 02/13/2025) and Brimble et al. (WO 2005023815 A2; previously cited by examiner).
Neuren discloses NNZ 2591, which has the following structure (p. 9).
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Neuren discloses that NNZ 2591 has been developed for the treatment of neurodevelopmental disorders, such as Phelan-McDermid syndrome, and has been granted a United States patent for a method of using NNZ 2591 to treat neurodevelopmental disorders (p. 4, p. 8). Neuren also teaches that NNZ 2591 normalizes depressed levels of IGF-1 in mouse models of Phelan-McDermid syndrome (p. 8). Neuren further discloses that NNZ 2591 is a synthetic analog of cyclic glycine-proline which is related to IGF-1, wherein cyclic clycine-proline regulates binding of IGF-1 to IGF binding protein 3 and in turn regulates bioavailability of IGF-1 (p. 9). Neuren teaches that NNZ 2591 mimics the natural function of cyclic glycine-proline in the brain with enhanced half-life in circulation, better stability, and suitability for use as an oral medication compared to its naturally occurring counterpart and IGF-1 (p. 9). Neuren additionally discloses that NNZ 2591 reduces levels of inflammatory cytokines which results in improvement in symptoms such as post-traumatic seizures, anxiety, memory impairment, and hyperactivity (p. 10).
Neuren does not teach administering NNZ 2591 for treatment of Prader-Willi syndrome, combining NNZ 2591 with another therapeutic agent, a dose of NNZ 2591, or and aqueous oral solution of NNZ 2591. These limitations are obvious in view of Heksch et al. and Brimble et al.
Hekcsh et al. teaches that Prader-Willi syndrome (PWS) is characterized by deficient IGF-1 levels in almost 100% of patients studied (p. 274-275). Treatment for PWS includes growth hormone (GH) therapy, wherein administration of GH helps to increase and maintain IGF-1 levels (p. 275).
Brimble et al. teaches neuroprotective bicyclic compounds, including the compound cyclic G-2allylP (p. 38) which is identical to NNZ 2591 as above.
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Brimble et al. teaches that the compound can be administered in combination with another neuroprotective agent, selected from growth factors and associated derivatives (insulin-like growth factor-I [IGF-I], insulin-like growth factor-II [IGF-II], transforming growth factor-/31, activin, growth hormone, nerve growth factor, growth hormone binding protein, IGF-binding proteins [especially IGFBP-3], basic fibroblast growth factor, acidic fibroblast growth factor, the hst/Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-induced growth factor. Additional members of the FGF family include, for example, int-2, fibroblast growth factor homologous factor- 1 (FHF-1), FHF-2, FHF-3 and FHF-4, keratinocyte growth factor 2, glial-activating factor, FGF- 10 and FGF- 16, ciliary neurotrophic factor, brain derived growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 [BMP-2], glial-cell line derived neurotrophic factor, activity-dependent neurotrophic factor, cytokine leukemia inhibiting factor, oncostatin M, interleukin), α-, β-, γ-, or consensus interferon, and TNF-α (p. 21). Brimble et al. additionally discloses that the compound may be administered orally at a suitable dose of 0.001 to 100 mg/kg (p. 19-2020) and suitable liquid carriers include water, saline, Ringer's solution, a buffered solution, and dextrose solution (p. 22). Brimble further states, “A person of ordinary skill in the art will be able without undue experimentation, having regard to that skill and this disclosure, to determine a therapeutically effective amount of a compound of this invention for a given disease or injury” (p. 19).
It would be prima facie obvious for one of ordinary skill in the art to administer NNZ 2591 for the treatment of Prader-Willi syndrome. One would be motivated to do so, with reasonable expectation of success, as NNZ 2591 is a neuroprotective compound that normalizes depressed levels of IGF-1, which is also a target in the treatment of Prader-Willi syndrome. One of ordinary skill in the art would be apprised that amelioration of low IGF-1 in patients would be beneficial in ameliorating Prader-Willi syndrome and its symptoms. Moreover, one of ordinary skill in the art would be apprised that combination of NNZ 2591 with another agent, such as growth hormone or IGF-1, would be expected to yield additive results by further improving IGF-1 levels.
It would be prima facie obvious for one of ordinary skill in the art to formulate a composition comprising NNZ 2591 as an aqueous oral solution, and/or to arrive at a dose of from about 0.001 mg/kg to about 600 mg/kg. One would have been motivated to do so, with reasonable expectation of success, in order to determine the optimal form of administration and/or dose. Moreover, an aqueous solution would be a pharmaceutically acceptable form for oral administration as suggested by Brimble et al., and the dose set forth by Brimble et al. of 0.001 to 100 mg/kg falls within the claimed range.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MADELINE E BRAUN whose telephone number is (703)756-4533. The examiner can normally be reached M-F 8:30am-5:00pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/M.E.B./Examiner, Art Unit 1624 03/24/2026
/BRENDA L COLEMAN/Primary Examiner, Art Unit 1624
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