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 .
Priority
The instant application, filed 05/02/2023, is a national stage entry of PCT/US21/57698, filed 11/02/2021, which claims domestic priority to U.S. provisional application number 63/145,681, filed 02/04/2021, and 63/1091 111, filed 11/03/2020.
Amendments and Claim Status
The amendment filed on 03/10/2026 is acknowledged and entered.
Claim 46 is amended;
Claims 1-46 and 47-72 are cancelled;
Claims 73-86 are added.
Claims 46 and 73-86 are pending and are under prosecution.
Information Disclosure Statement
The Information Disclosure Statement filed on 12/01/2023, 05/15/2025, and 03/10/2026 are acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the information disclosure statements are considered.
Restriction/Election
Applicant’s election without traverse of Group I in the reply filed on 03/10/2026 is acknowledged. The additional election of cilnidipine as a specific compound of Formula (I), and Duchenne muscular dystrophy as the specific disease to be treated, are also acknowledged.
In accordance with the MPEP § 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non-elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be reexamined. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during reexamination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
As per MPEP § 803.02, the Examiner will determine whether the entire scope of the claims is patentable. Applicants' elected species do not make a contribution over the prior art of record. Furthermore, it has been determined that the entire scope claimed is not patentable.
Status of Claims
Claims 46 and 73-86 are pending in the instant application. Claims 74 and 80 are withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species. Therefore, claims 46, 73, 75-79, and 81-86 read on an elected invention and species and are therefore under consideration in the instant application.
Drawings
The drawings filed on 05/02/2023 are found to be in compliance with 37 CFR §§ 1.121 and 1.84, and are hereby accepted.
Claim Rejections - 35 U.S.C. § 112
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 46, 73, 75-79, and 81-86 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. § 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 46, 73-80, and 84-86 of the instant application are drawn to the administration of compounds having following substituents:
R1 is phenyl substituted with one to three substituents each of which is independently NO2, NH2, OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyalkyl, provided that at least one substituent is NO2 or NH2;
R1b and R1c are each independently H, NO2, NH2, OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyalkyl;
R2 is H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyalkyl;
R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyalkyl;
R4 is C1-C6 alkyl or C1-C6 haloalkyl;
R5 is phenyl or pyridinyl, wherein the phenyl or pyridinyl is substituted with one to three substituents each of which is independently NO2, NH2, OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyalkyl;
m is an integer from 1 to 4;
n is an integer from 1 to 3;
35 U.S.C. § 112(a) and the first paragraph of pre-AIA 35 U.S.C. § 112 require that the "specification shall contain a written description of the invention ...." This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc); Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111,1114 (Fed. Cir. 1991); see also Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004) (discussing the history and purpose of the written description requirement); In re Curtis, 354 F.3d 1347, 1357, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) ("conclusive evidence of a claim’s enablement is not equally conclusive of that claim’s satisfactory written description"). The written description requirement has several policy objectives. "[T]he ‘essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant has invented the subject matter which is claimed." In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert, denied, 523 U.S. 1089 (1998). "The ‘written description’ requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005). Further, the written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent’s term.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaffv. Wells Bees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); EliLilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm.,927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991). An application specification may show actual reduction to practice by describing testing of the claimed invention.
In the present case, the important factors leading to a conclusion of inadequate written description is the absence of any working example of the invention as claimed, and the lack of predictability in the art.
In the instant specification, there is no disclosure of compounds having the following claimed substituents:
R1 as phenyl substituted with one to three substituents each of which is independently OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyalkyl;
R1b and R1c as NO2, NH2, OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyalkyl;
R2 as H, C2-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyalkyl;
R3 as H, C2-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyalkyl;
R4 as C2-C6 alkyl or C1-C6 haloalkyl;
R5 as phenyl or pyridinyl, substituted with one to three substituents each of which is independently NO2, NH2, OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxyalkyl;
m as an integer of 1, 3, or 4;
n as an integer of 2 or 3;
The instant specification (pages 6 and 7) teaches compounds which are characterized as having only the following substituents:
R1 is phenyl substituted with either NO2 or NH2,
R1b and R1c are H
R2 is CH3
R3 is CH3
R4 is CH3
R5 is unsubstituted phenyl or pyridinyl
m is 2
n is 1
Therefore, the methods described in the instant specification detail only a limited number of the total compounds and substituents claimed (see substituents 1-8, above). All working examples presented in the instant specification are related to the compounds containing a fraction of the total claimed substituents (see substituents 17-24, above).
There are no working examples in the instant specification for the wide range of substituents claimed, but for which evidence of possession has not been provided (see substituents 6-16, above). Thus the instant specification does not provide any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application.
Vas-Cath Inc. Mahurkar, 19 USPQ2d 1111, makes clear the "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F. 3d 1565, 1572, 41 USPQ2d 1961, 1966(1997); In re Gosteli, 872 F.2d 1008, 1012,10 USPQ2d 1614, 1618 (Fed Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.") Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. For example, disclosure of only a method of making the invention and the function may not be sufficient to support a product claim other than a product-by-process claim. See, e.g., Fiers v. Revel, 984 F.2d at 1169, 25 USPQ2d at 1605; Amgen, 927 F.2d at 1206, 18 USPQ2d at 1021.
Thus, since Applicant has not described in adequate detail methods to synthesize compounds containing the claimed substituents, or provided evidence that said compounds have been characterized, or that they exist, an ordinary skilled artisan could not completely envisage Applicants’ invention. Moreover, it is clear that the written description requirement has not been met since Applicant has not provided any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application. Thus, claims 46, 73, 75-79, and 81-86 of the instant application are not supported by the instant specification and thus a rejection under 35 U.S.C. § 112 (a) for failing to comply with the written description requirement is proper.
Claim Rejections - 35 U.S.C. § 103
The following is a quotation of pre-AIA 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.
Claims 46, 73, 75-79, 81-83, and 85 are rejected under 35 U.S.C. § 103 as being unpatentable over Nishida et al. (WO 2016080516 A1, published August 31, 2017), hereinafter Nishida, in view of Scholtes et al. (Scientific Reports, Volume 8, Article number 7354, published May 9, 2018), hereinafter Scholtes.
The instant claims are drawn to a method of treating a human subject having Duchenne muscular dystrophy (DMD) comprising the administration of cilnidipine or a pharmaceutically acceptable salt or solvate thereof.
Nishida teaches a Drp1 polymerization inhibitor comprising cilnidipine as the active ingredient. Nishida discloses that cilnidipine suppresses pathological mitochondrial fission, and discloses pharmaceutical compositions comprising cilnidipine for treating diseases driven by aberrant Drp1 activity (pages 3-5, and claims 1-6).
Nishida fails to teach the use of cilnidipine for treating Duchenne muscular dystrophy as the specific disease driven by aberrant Drp1 activity.
The deficiencies of Nishida are remedied by Scholtes, who teaches that Drp1 is a causative driver of dystrophin-dependent muscle degeneration (page 2), wherein DYS-1 is the homolog of dystrophin in mammals, making it a direct model of human DMD (pages 2, 10, and 11). Specifically, Scholtes discloses that loss of Drp1 function in dystrophin deficient mutants significantly reduced mitochondrial fragmentation, apoptotic muscle cell death, and the number of abnormal muscle cells (Abstract, pages 10 and 11). Scholtes further notes that DRP-1 levels are upregulated in mouse DMD models and that elevated Drp1 activity has been documented in biopsies from human DMD patients (page 3). The disclosure concludes that Drp1 inhibition represents a promising target for treatment of human DMD (page 11).
A person having ordinary skill in the art, prior to the effective filing date of the instant claims, would have been motivated to combine the teachings of Nishida, identifying cilnidipine as a clinically approved Drp1 inhibitor, with the teachings of Scholtes, who identifies Drp1 over activation as a causal mechanism of DMD muscle degeneration, in order to develop a treatment for human DMD. A person having ordinary skill in the art would have immediately recognized administering a known Drp1 inhibitor to treat a disease causally driven by Drp1 over activation represents an obvious therapeutic application, with a reasonable expectation of success given the established clinical safety of cilnidipine established by Nishida, to be used as a target for Drp1 inhibition for muscular dystrophy treatment as taught by Scholtes.
Regarding claim 85, phagocytic deficiency is an inherent characteristic of Duchenne muscular dystrophy, as taught by Scholtes (page 11). Specifically, Scholtes teaches that increased calcium production which results from dystrophin deficiencies of DMD impair autophagy, demonstrating that a human affected by DMD will inherently have a phagocytic deficiency.
The teachings are individually applied to the claims, and the instant claims herein stand rejected.
Claim 84 is rejected under 35 U.S.C. § 103 as being unpatentable over Nishida in view of Scholtes (as applied to claims 46, 73, 75-79, 81-83, and 85, above), and further in view of Siegel et al. (Neuromuscular Disorders, Volume 19, pages 131–139, published December 2, 2009), hereinafter Siegel.
The instant claim is further drawn to a formulation of a compound of Formula (I) further comprising ursodeoxycholic acid.
Nishida and Scholtes are as set forth above.
Nishida and Scholtes fail to teach a formulation further comprising ursodeoxycholic acid.
The deficiencies of Nishida and Scholtes are remedied by Siegel, who teaches that ursodeoxycholic acid, when administered in vivo to dystrophic mdx mice, directly improves whole-body tension development in the DMD model by acting as an NF-kB inhibitor (pages 132-134). Siegel explicitly teaches that the mdx mouse is a useful model for Duchenne muscular dystrophy, because it exhibits many of the phenotypic characteristics of human muscular dystrophy (page 131).
A person of ordinary skill in the art would be motivated to combine the use of cilnidipine in the treatment of muscular dystrophy as taught by Nishida and Scholtes, with ursodeoxycholic acid as taught by Siegel, because both compounds demonstrate independent therapeutic benefit in DMD through complementary mechanisms. Cilnidipine targets Drp1-mediated apoptosis while ursodeoxycholic acid targets NF-kB driven inflammation. Therefore, a person of ordinary skill in the art would have found it obvious to combine cilnidipine with ursodeoxycholic acid for the purpose of treating DMD.
In further support of the obviousness conclusion, the combination of two known entities used for the same purpose, i.e. the treatment of DMD, is considered prima facie obvious. According to MPEP § 2144.06 (I), combining equivalents known for the same purpose is rendered obvious. The courts have said,
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.).
Therefore,, a person of ordinary skill in the art would have found it obvious to combine cilnidipine with ursodeoxycholic acid, for the common purpose of treating DMD.
Claim 86 is rejected under 35 U.S.C. § 103 as being unpatentable over Nishida in view of Scholtes (as applied to claims 46, 73, 75-79, 81-83, and 85, above), and further in view of Yasmineh et al. (Clin Chem, Volume 24, Issue 11, pages 1985-1989, published November 1, 1978), hereinafter Yasmineh.
The instant claims are drawn to administering cilnidipine in an amount effective to reduce creatine kinase and/or lactate dehydrogenase in the plasma of a DMD subject.
Nishida and Scholtes are as set forth above.
Nishida and Scholtes fail to teach administering cilnidipine in an amount effective to reduce creatine kinase and/or lactate dehydrogenase in the plasma of a DMD subject.
The deficiencies of Nishida and Scholtes are remedied by Yasmineh, who establish that serum creatine kinase and lactate dehydrogenase are routine biochemical outcome measures used to assess the progression of DMD (Title). Specifically, Yasmineh teaches that both creatine kinase and lactate dehydrogenase are found to be elevated in the plasma of patients with DMD.
A person of ordinary skill in the art would have been motivated to combine the teachings of Nishida and Scholtes with those of Yasmineh, because creatine kinase and lactate dehydrogenase are universally recognized biomarkers of skeletal muscle damage in DMD. As such, the reduction is the expected pharmacodynamic consequence of any agent that reduces muscle degeneration, and the measurement as a therapeutic endpoint in DMD is well-established in the art. A person having ordinary skill administering cilnidipine to a DMD patient for the purpose of producing Drp1-mediated muscle degeneration would inherently inspect and routinely measure creatine kinase and practice dehydrogenase reduction is a confirmation of therapeutic efficacy.
Correspondence
No claim is allowed.
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
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