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 .
Application Status
The action is written in response to applicant’s correspondence received 10/10/2025. Claims 1-21 are currently pending in the instant application.
Claims 1-21 are under examination on the merits in the instant case.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The priority date is August 8, 2022.
Claim interpretation: Claims 1-3 recite a method for increasing skeletal muscle mass, skeletal muscle wasting, and improving mitochondrial function, respectively, wherein said method comprises of any means to inhibit site-1 protease. These claims have been interpreted to encompass a method of treatment since all the claims recite the same step of inhibiting site-1 protease in skeletal muscles of the subject.
Claim Rejections - 35 USC § 112
Written Description
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 1-21 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.
The factors to be considered when analyzing claims for compliance with the written description requirement include: (A) actual reduction to practice; (B) disclosure of drawings or structural chemical formulas; (C) sufficient relevant identifying characteristics (e.g., complete structure, partial structure, physical and/or chemical properties, structure/function correlation); (D) level of skill and knowledge in the art; and (E) predictability in the art.
Each of the factors (A)-(E) listed above is analyzed below
As instantly presented, claims encompass a method of inhibiting site-1 protease in skeletal muscles wherein the inhibiting agent can be any inhibitor, a genetic construct that reduces site-1 protease protein levels, any small molecule inhibitor of site-1 protease, and a combination of any of these. Claims therefore encompass a broad genus of molecules that include any genetic construct or any small molecule or any inhibitor.
The specification has mentioned that term inhibiting site-1 protease on pages 1, 2, 6, 7, 8, 9, and 10. Except for the protease inhibitor PF-429242, there is no other description of any inhibitor of site-1 protease. While, claim 7 recites a construct comprising CRISPR/Cas9 or siRNA, however, there is no description of the construct or the elements of the construct.
(A) actual reduction to practice
The instant specification does not disclose an actual working example for the instantly claimed method for “increasing skeletal muscle mass”, “treating skeletal muscle wasting”, or “improving mitochondrial function in skeletal muscle”, where the method comprises “inhibiting site-1 protease” in the skeletal muscle of the subject where the method is CRISPR/Cas9 or siRNA inhibition. The specification discloses examples of site-1 protease targeting siRNAs in C2C12 cells as well as experimental data done in mice with a site-1 protease knockout in the skeletal muscle of said mice (see paragraph 0020, 0029, figure 1I, and figure 3D of the specification). However, the specification does not disclose any siRNA or small molecule S1P inhibitor. SiRNA experiments on an in vitro cell line and gene deletion in mice, described in paragraph 0046 of the specification, does not provide any description of the structure or elements of a genetic construct or the structure of a small molecule inhibitor used.
(B) disclosure in drawings or structural chemical formulas
While the drawings show results of experiments, there is no description of any site-1 protease inhibitors. While the instant application lists sequences of SEQ ID NOs: 1-24, the specification does not provide any specific guidance regarding the sequences structure of any specific CRISPR/Cas9 or siRNA molecules. Furthermore, the applicant does not disclose any chemical structure for a small molecule inhibitor recited in claim 6.
(C) sufficient relevant identifying characteristics (e.g., structure/function correlation).
The instant specification does not provide any written description support for the required structure-function correlation for the method of inhibiting site-1 protease in the skeletal muscle of a subject. There are no specific SEQ ID NOs for modified gRNAs, novel siRNAs, or chemical structures mentioned that are required to provide the following functionalities/effects.
(D) level of skill and knowledge in the art
The instant application recites a method for inhibiting site-1 protease in the skeletal muscle of the subject that is a domesticated animal or human. The knowledge and skill level of an artisan working in this area is high.
(E) predictability in the art
The state of the art teaches only one small molecule site-1 protease inhibitor that is PF-429242. For example, Hawkins et al. teaches inhibition of site-1 protease by PF-429242. No other small molecule inhibitors are described in the art. There is no evidence that the structure of PF-429242 is a representative structure of small molecule inhibitors encompassed by claimed invention.
In view of the totality of factors analyzed above, it is clear that the instant specification fails to reasonably convey that the instant inventors had possession of the instantly claimed subject matter as of the effective filing date.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 3, 6-9, and 16-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US patent publication Brookheart et al. (US 2020/0215032 A1).
Regarding claims 3, 6-9, and 16-17, Brookheart taught a method of administering “a S1P inhibiting agent” to mice where the “S1P inhibiting agent is selected from a small molecule inhibitor of S1P” and resulted in improving exercise endurance in a subject that exhibits a disease associated with disrupted skeletal muscle function or metabolism or an increase mitochondrial function in the soleus (see paragraph 008, 0011, 0014, 0029 as well as claims 17 and 21).
Absent evidence to the contrary, this method would result in improving mitochondrial function in a subject because the method of Brookheart has the same steps as the instantly claimed application method and is therefore considered to provide the effects recited in the preambles of the instant claims regarding treating skeletal muscle wasting. If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. See MPEP 2111.2 and 2112. Thus, Brookheart clearly anticipate instant claims 3, 6-9, and 16-19.
Claims 6, 7, 8, and 9 are anticipated because the specification of Brookheart recites a genetic construct for the use of site-1 protease inhibition that can include a siRNA system (see paragraph 0020). Administration occurs within the skeletal muscle and can occur over a single administration, or over multiple administrations throughout a time period (see paragraph 0103).
Claims 16 and 17 are anticipated because Brookheart recites intramuscular injection in the skeletal muscle of mice which would include the muscle groups listed in claim 16, as well as where the subject is a mammal (see paragraph 0095).
Claims 18 and 19 are included because Brookheart recites improving muscle endurance for an athlete which encompasses a domesticated animal or human.
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.
Claims 1-2, 4-5, 10 -15 and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Brookheart et al. (US 2020/0215032 A1) in view of Gianola et al., Brown et al., Wang et al., Medinas et al., Moyer et al., Bowen et al., and Nakamura et al.
The teachings of Brookheart are described as above. Briefly, Brookheart teaches treating subjects with a site-1 protease inhibitor to improve exercise endurance, performance, or tolerance within a subject that has a site-1 protease mutation. The method teaches administering a site-1 protease inhibitor intramuscularly within a subject and to improve skeletal muscle function or metabolism or mitochondrial function.
Brookheart did not teach a method for increasing skeletal muscle mass or treating skeletal muscle wasting in a subject in need thereof. Brookheart does not teach a method of improving mitochondrial function where the skeletal muscle comprises of glycolytic muscle fibers and wherein the method results in reduced MSS51 expression. Brookheart did not teach wherein the subject has sarcopenia, cachexia, chronic kidney disease, a muscular dystrophy, or a combination thereof. Brookheart also does not teach whether the patient is geriatric, over the age of 60-90, or wherein the subject does not have a site-1 protease mutation.
Gianola studied the effects of muscular exercise on patients with muscular dystrophy. Based on the study, Gianola concluded that while muscular exercise is not associated with an improvement in strength, it does improve endurance during walking comparing patients with and without treatment plans. See outcomes and discussion section. This study shows that if exercise endurance can be improved, and patients can exercise more, it could further improve muscle conditioning in patients with muscular dystrophy. Therefore, it would be obvious to use a method for improving exercise endurance to increase muscle mass or treat a muscle wasting disease.
At the time of the filing of the invention, the role of site-1 protease in the regulation of MSS51 was well known in the art. For example, as discussed below, art taught site-1 protease regulated SREBP pathway which mediates TGF-β upregulation that in turn induces skeletal muscle atrophy and fibrosis.
Brown teaches site-1 protease is a key player in the sterol regulatory element-binding proteins (SREBPs) pathway which regulates lipid synthesis (see abstract).
Wang teaches SREBP-1 mediates angiotensin II-induced transforming growth factor – beta 1 (TGF-β1) upregulation (see abstract and results section).
Medinas teaches that TGF-β induces skeletal muscle atrophy and fibrosis. TGF-β is a well-known regulator of fibrosis and inflammation in many tissues. The upregulation of TGF-β is shown to induce muscle atrophy and cause a dramatic reduction in the force generating capacity of otherwise healthy muscle (see discussion section).
Furthermore, relationship of MSS51 in skeletal muscle physiology and metabolism was well known as discussed below.
Moyer teaches that MSS51 is a skeletal muscle-specific gene that is a key target of myostatin and TGF-β1 signaling. Furthermore, Moyer teaches MSS51 expression is predominantly seen in glycolytic skeletal muscle (see conclusion section and figure 3).
Bowen teaches skeletal muscle wasting caused by cachexia is associated with chronic disease like cancer as well as inflammatory conditions such as heart failure and chronic kidney disease. Bowen also teaches sarcopenia is characterized by the slow and progressive loss of muscle mass associated with ageing in the absence of any underlying disease or condition. The prevalence of sarcopenia ranges from 15% at 65 years old to 50% at 80 years in humans. Furthermore, Bowen teaches that sarcopenia and cachexia can often run in parallel where elderly patients with sarcopenia are also diagnosed with a cachectic condition. See introduction section.
Nakamura teaches that the main cause of DMD is a mutation in the DMD gene resulting in a decrease in the expression of dystrophin. This study emphasized that the main cause of DMD is not a site-1 protease mutation, but a mutation in the DMD gene. See introduction and discussion section.
It would have been obvious to one of ordinary skill in the art at the time of the invention to administer an inhibitor of site-1 protease to a subject for improving mitochondrial function in the skeletal muscle of the subject where the skeletal muscle comprises of glycolytic muscle fibers and results in reduced MSS51 expression with a reasonable expectation of success. An artisan would have been motivated to do so because inhibiting site-1 protease would have resulted in the decrease of MSS51 expression in skeletal muscles of the subject. As taught by Brown, Wang, Medinas, and Moyer, MSS51 is inherently part of the same pathway that regulates muscle growth and proliferation. MSS51 is a target gene of TGF-β, which is regulated by SREBPs that is further regulated by site-1 protease. Improved mitochondrial function is associated with an increase in muscle mass and a part of treating a skeletal muscle wasting disease.
It would have been similarly obvious to use a method of improving mitochondrial function by administering an inhibitor of site-1 protease to treat muscle wasting diseases caused by DMD, sarcopenia, and cachexia. As discussed by Bowen, patients who are geriatric (over the age of 65) are more predisposed to muscle wasting diseases, one would have been motivated to use this method as a treatment on older individuals. In addition, DMD is caused by a mutation of the DMD gene, while sarcopenia is associated with ageing, and cachexia is associated with chronic illnesses such as cancer. It would not be necessary for the individual being treated to have a site-1 protease mutation.
In view of the foregoing, claims 1-2, 4-5, 10 -15 and 20-21, taken as a whole, would have been prima facie obvious before the effective filing date.
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 1-21 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 3, 6 and 8 of U.S. Patent No. 11534423B2. Although the claims at issue are not identical, they are not patentably distinct from each other because;
Claims 1-21 of the instant application recite a method for increasing skeletal muscle mass, treating a skeletal muscle wasting disease, or improving mitochondrial function by administering a site-1 protease inhibitor. Claims 1, 3, 6 and 8 of the issued patent recite a method of improving exercise tolerance in a subject or a method of treating a disease, or disorder associated with reduced exercise tolerance or endurance in a subject comprising administering a pharmaceutical composition comprising of a site-1 protease inhibiting agent. The patented claims are encompassed by the broad claims of the instant application.
Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
Conclusion
No claim is allowed.
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/D.T.Y./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635