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 .
DETAILED ACTION
Applicant’s response and claim amendments filed on 5/8/2026 are received and entered.
In response to the most recent action, claims 1-3, and 7 have been amended and are currently pending. Claim 4 has been cancelled.
Claims 1-3 and 5-21 are currently pending and under examination of the merits.
Any rejections/objections NOT repeated/presented here are withdrawn.
Maintained Rejections
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. Furthermore, the use of any siRNA to target a specific sequence is unpredictable. As disclosed by Tao et al., target genes are targeted with specific sequences and gRNA and wherein siRNAs or CRISPR-Cas9 systems that incorrectly bind to untargeted genes generate unpredictable results (see introduction). Therefore, objective testing of a specific siRNA is important as gene editing itself is unpredictable.
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.
Response to Arguments
Applicant’s arguments filed on 5/8/2026 have been fully considered but they are not persuasive. Applicant argues that the specification provides extensive disclosure for demonstrating the inventor had actual possession of methods for inhibiting site-1 protease in skeletal muscle to achieve the claimed therapeutic effects, such as generation of S1PsmKO mice by crossing S1P floxed mice with HAS-Cre79, confirmation of S1P mRNA reduction in gastrocnemius, soleus, and other skeletal muscles, increase muscle mass in S1PsmKO mice, enhanced mitochondrial respiration, etc. Furthermore, applicant argues siRNA knockdown of S1P in C2C12 myofiber cells, the use of custom siRNAs targeting S1P with Lipfectamine RNAiMAX transfection, etc. Applicant also argues that the specification needs not “reiterate the structure or formula or chemical name for nucleotide sequences” where genes were novel combinations of known DNA segments or where “the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function”. Applicant further argues that the office’s citation of Hawkins et al. confirms that PF-429242 is known pharmacologic inhibitor of S1P and one skilled in the art would recognize that fatostatin and botulin were known compounds in this class of inhibitors. Applicant finally argues that the novelty and inventive contribution lies in the discover that site-1 protease inhibition in skeletal muscle produces these specific therapeutic effects.
Applicant’s arguments are not persuasive because although applicant show the therapeutic effects of S1P inhibition, applicant does not show possession of any small molecule inhibitor or the combination of a specific genetic construct with a small molecule inhibitor. For the example presented of S1P floxed mice, the specification describes the mice were obtained from other parties and referencing Yang et al. which describes the generation of such mice through the floxing, or the introduction of cre-lox sites around a gene to regulate gene expression (see paragraph 0088). However, this provides no evidence or reduction to practice that the inventors had possession of a method of inhibiting for generating a S1P KO in mice using siRNA or CRISPR/Cas9, only reciting a known method in the art. With regards to PF-429242, fatostatin, and betulin being in the same class of inhibitors, these three small molecule inhibitors are not representative of the broad genus of all small molecule inhibitors. Though in vitro cell line experiments do show S1P mRNA reduction following siRNA treatment, it is known to one skilled in the art that the function/activity of individual gRNAs and siRNAs was known to be highly unpredictable unless actually made and tested with objective evidence. For example, Tao et al. (Application of Nanoparticle-Based siRNA and CRISPR/Cas9 Delivery Systems in Gene-Targeted Therapy, Nanomedicine, Volume 14, Issue 5, published 2019) teaches where siRNAs or CRISPR-Cas9 systems may incorrectly bind to untargeted genes and generate unpredictable mutations, mismatches, or deletions that are outside of the targeted site (see introduction). Merely testing commercial siRNA from Life Technologies, wherein the commercial siRNA that was tested and known to work is not a representative number of species of all siRNAs targeting S1P. Therefore, the structure and function of said siRNAs cannot be well-established if there is high unpredictability without testing.
Furthermore, regarding the novelty of the therapeutic effects, if applicant intends to argue such effects are novel due to the targeting of S1P, and not the novelty of the composition used, one skilled in the art would recognize that S1P as a target would be largely unexplored, as if it was a well characterized target, the prior art could disclose potential therapeutic applications. Therefore, targeting the specific sequence of S1P with siRNA or any small molecule inhibitor is not well known, and requires proper disclosure of structure adequate to support possession of the invention
In view of the foregoing, the written description rejection is upheld.
New Rejections
Claim Rejections - 35 USC § 103
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, 8-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Brookheart et al. (US 2020/0215032 A1, published 7/9/2020) in view of Graham et al. (Mechanisms of exercise as a preventative measure to muscle wasting, Am. J. Physiol. Cell Physiol., Volume 321, Issue 1, published May 5, 2021) and Cohen et al. (Muscle wasting in disease: molecular mechanisms and promising therapies, Nature Reviews Drug Discovery, Volume 14, pgs. 58-74, published 2015).
Regarding claim 1-2, Brookheart teaches a method which recites the administration of a Site-1 Protease (S1P) inhibitor to a subject, in order to improve exercise tolerance or enhance exercise performance (see paragraph 0007), wherein in some embodiments, the subject has or is suspected of having a disease, disorder, or condition associated with exercise tolerance such as mitochondrial disorders or diseases, cardiovascular diseases, reduced skeletal muscle function, disrupted skeletal muscle function or metabolism…etc. (see paragraph 0014 and claim 8).
Brookheart further teaches wherein the S1P inhibitor can be siRNA (see claim 14) or an S1P inhibiting agent such as PF-429242 (see claim 16)
Regarding claims 1-2, Brookheart teaches where the administration can be intramuscular (see paragraph 0097).
Regarding claim 8, Brookheart teaches where administration of the methods described can be direct injection (see paragraph 0108) and discloses where the administration can be intramuscular (see paragraph 0097). Therefore, one skilled in the art would find that the composition of the instant method can be administered directly to the skeletal muscle of a subject.
Regarding claim 9, Brookheart teaches where administration of an S1P inhibiting agent can occur as a single event or over a time course of treatment. For example, an S1P inhibiting agent can be administered daily, weekly, bi-weekly, or monthly (see paragraph 0103).
Regarding claim 11, Brookheart teaches where the subject in need thereof has chronic muscle fatigue, reduced skeletal muscle function, disrupted skeletal muscle function, or dysfunctional muscle (see claim 8).
Regarding claims 1-2, Brookheart does not teach wherein the administration of a S1P inhibitor to the skeletal muscle of a subject results in increasing skeletal muscle mass in a subject in need thereof or as a method for treating skeletal muscle wasting diseases in a subject in need thereof.
Regarding claim 10, Brookheart does not teach where the subject is geriatric.
Regarding claim 11, Brookheart does not teach where the subject has a skeletal muscle wasting disease.
Regarding claims 12-14, Brookheart does not teach where in the method of claim 2, a method for treating a skeletal muscle wasting disease, the subject has specific muscle wasting diseases such as sarcopenia, cachexia, chronic kidney disease, a muscular dystrophy, or a combination thereof.
Regarding claims 1-2, Graham teaches a review analyzing the role of exercise in altering the molecular landscape of skeletal muscle in a manner that improves or maintains its health and function in the presence of unloading or disease (see abstract). Graham teaches where exercise training has been established as an efficacious and multipotent health intervention that can limit or treat the development of cognitive, psychological, cardiovascular, musculoskeletal, metabolic, and age-related disease, as well as many cancers (see background). Graham teaches where the ability of exercise to prevent or slow disease states is intimately related to its ability to prevent or slow muscle wasting (see introduction). Furthermore, Graham teaches where the power of exercise and relative ease of accessibility clearly implicate exercise as a crucial frontline intervention to treat muscle loss in many disease states and wherein cases where unloading and disuse atrophy are predicted, prescribed exercise to increase muscle mass and combat muscle loss should be considered (see conclusion).
Regarding claim 13, Graham also makes note that individuals with DMD exhibit biomarkers that are associated with muscles under conditions of atrophy or damage (see section titled epigenetics).
Regarding claims 10-12, and 14-15, Cohen teaches a systematic review of muscle wasting in diseases. Cohen teaches where muscle wasting can occur systemically in older people, such as those who are geriatric, (a condition known as sarcopenia), cancer-associated cachexia, renal failure, cardiac failure, etc. (see abstract).
It would have been obvious to one skilled in the art, before the effective filing date, to combine the teachings of Brookheart, Graham, and Cohen to arrive at a method for increasing skeletal muscle mass in a subject in need thereof or for treating skeletal muscle wasting in a subject in need thereof.
One would be expected a reasonable chance of success as Brookheart teaches the method of the instant application, which is administering a S1P inhibitor such as siRNA, an agent, or a combination of both to a subject in need thereof, results in improved exercise tolerate or improved exercise endurance of a subject (see claim 3), showing that S1P inhibition leads to a positive effect on systems associated with muscle atrophy. Furthermore, the subject in question of the instant claim 1 and 2 is broad, simply reciting where the subject is “in need thereof”, wherein Brookheart specifies the subject in question has…chronic muscle fatigue, reduced skeletal muscle function, disrupted skeletal muscle function or metabolism…, or dysfunctional muscle (see claim 8 of Brookheart), therefore the subject of Brookheart would display the same conditions as a subject of the instant application.
One would be motivated to do so as Brookheart teaches “S1P plays an important role in regulating skeletal muscle mitochondrial metabolism and influencing the endurance for exercise (see paragraph 0131). Graham teaches endurance exercise is a method of treatment in treating a subject which is predicted to have muscle atrophy, where these subjects could have a variety of diseases as evidenced by Cohen, wherein endurance exercise results in an increase of muscle mass and combats muscle loss (see conclusion). One skilled in the art would recognize that by increasing the ability of exercise endurance in a subject through the method of Brookheart, one would see an increase in muscle mass and combating muscle loss through increased exercise, which is described by Graham, in subjects that could have muscle wasting diseases that are described in Brookheart and Cohen.
In view of the foregoing, claim 1-2, 8-15 are rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
Response to Arguments
Applicant’s arguments filed on 5/8/2026 have been fully considered but they are not persuasive. Regarding claims 1-2, applicant argues that Brookheart does not teach “a method for increasing skeletal muscle mass”, or “treating a muscle wasting disease. Applicant further argues that the secondary reference of Gianola does not alleviate the deficiencies of Brookheart as Gianola expressly teaches “exercise is not associated with an improvement in strength”. Applicant further asserts the examiner’s rejection combines eight separate references to arrive at the claimed invention and where none of the cited reference demonstrate or suggest these therapeutic outcomes as described in the instant application. Furthermore, no secondary reference teach that S1P inhibition would be therapeutic for said conditions, where the mere identification of disease pathology does not provide a reasonable expectation that a particular intervention (S1P inhibition) would successfully treat those diseases.
Though applicant is correct in asserting Gianola does not teach where exercise is associated with an improvement in strength, this argument is rendered moot in view of Graham. Regarding claims 1 and 2, Graham teaches the role of exercise in maintaining health of skeletal muscles in the presence of unloading or diseases. Though Graham does not teach S1P inhibition, Brookheart teaches S1P inhibition leads to an improvement of exercise tolerance or exercise performance, wherein cases where unloading and disuse atrophy are predicted, prescribed exercise to increase muscle mass and combat muscle loss should be considered. Therefore, the improvement of exercise is the nexus that links the known outcome of enhanced mitochondrial metabolism to the obvious outcome of increasing muscle mass and treating muscle wasting. As the subjects of Brookheart and the instant application overlap (as the instant application recites a subject in need thereof, which is broad, and Brookheart recites wherein the subject can have disrupted skeletal muscle function or dysfunctional muscle), a subject of Brookheart with said conditions would expect to see an improvement in exercise, which will inevitably lead to an increase of muscle mass or treatment of muscle wasting through exercise, as evidenced by Graham.
The use of Bowen and Nakamura in the pervious action indicates that muscle wasting are known symptoms of diseases such as DMD, sarcopenia, or cachexia. This is best summarized in one art in this instant action wherein Cohen teaches a systematic review of muscle wasting diseases. Though Cohen does not teach inhibitors are used to treat these diseases, it is already known that S1P inhibitors improve exercise performance, and exercise is well established in the art to be effective treatments for muscle wasting diseases to increase muscle mass or prevent muscle wasting, then the obvious rationale to combine these arts relates to the fact that the ability to perform exercise effective would eventually lead to these therapeutic outcomes.
Regarding applicant’s claim where prior to the present invention, there was no recognition in the art that: S1P inhibition prevents age-associated muscle mass loss, or where S1P inhibition could be used to treat sarcopenia, cachexia, or DMD, the prior art already establishes where S1P inhibition improves mitochondrial function specifically for exercise enhancement. As it is well known in the art that exercise is one of the main prescribed treatments for muscle wasting diseases, one skilled in the art would recognize that S1P inhibition increasing exercise tolerance or performance would lead to therapeutic outcomes of claims 1 and 2, as a result of the improved capacity for exercise.
Claim(s) 3, 5-7, 16-21 are rejected under 35 U.S.C. 103 as being unpatentable over Brookheart et al. (US 2020/0215032 A1, published 7/9/2020), Schiaffino et al. (Fiber Types in Mammalian Skeletal Muscles, Physiological Reviews, Volume 91, Issue 4, published 2011), Wang et al. (SREBP-1 is a novel mediator of TGFβ1 signaling in mesangial cells, JMCB, Volume 6, Issue 6, pgs. 516-530, published 10/26/2014), Moyer et al. (Mammalian MSS51 is a Skeletal Muscle-Specific Gene Modulating Cellular Metabolism, Journal of Neuromuscular Disease, Volume 2, Issue 4, published 9/21/2015) and Cohen et al. (Muscle wasting in disease: molecular mechanisms and promising therapies, Nature Reviews Drug Discovery, Volume 14, pgs. 58-74, published 2015).
Regarding claim 3, Brookheart teaches a method for improving mitochondrial function (see claim 3 wherein administration of the agent results in “enhanced mitochondrial metabolism”) in a subject in need thereof, wherein S1P protease is inhibited in the skeletal muscle of a subject. Brookheart teaches where the methods to inhibit S1P can be administered intramuscularly (see paragraph 0097) and through direct injection (see paragraph 0108).
Regarding claim 6, Brookheart teaches where the therapeutically effective amount of the pharmaceutical composition comprising a S1P inhibiting agent results in reduced or depleted S1P levels or reduced or depleted S1P activity (see paragraph 0008). Brookheart further teaches where the discovery of the invention presents that deactivation of S1P in the skeletal muscle increases exercise endurance (see paragraph 0039). Finally, Brookheart teaches where the S1P inhibitor can be a genetic construct (see claim 13) or an small molecule inhibiting agent such as PF-429242 (see claim 16).
Regarding claim 7, Brookheart teaches methods described herein can comprise a method for altering a target polynucleotide sequence in a cell comprising contacting the polynucleotide sequence with a Cas protein (see paragraph 0084) and where genome editing can knock out, knock down, or be any mutation that prohibits normal function of the S1P gene or results in a S1P deficiency or depletion (see paragraph 0085).
Regarding claim 17-19, Brookheart teaches where the subject is a mammal, such as a human, horse, or dog (see claim 23).
Regarding claim 21, Brookheart teaches in some embodiments, the subject has a gain of function mutation or a missense mutation in S1P transmembrane domain (see paragraph 0012). However, this only applies to some embodiments and the broader claim 1 of Brookheart which discloses a method of improving exercise tolerance in merely a subject and where the narrower dependent claim 6 indicates the subject has a mutation of S1P. Furthermore, Brookheart discloses Fig. 14 where wildtype mice were treated with a S1P inhibitor, and subjected to acute exercise test to exhaustion where wild-type mice displayed enhanced exercise tolerance compared to WT littermates (see paragraph 0216 and 0217).
Regarding claim 3, Brookheart does not directly teach where the skeletal muscle comprises glycolytic muscle fibers, but does teach where S1P mRNA levels are reduced in the gastrocnemius following S1P KO.
Regarding claim 5, Brookheart does not teach where the method results in reduced MSS51 expression.
Regarding claim 16, Brookheart does not teach where the skeletal muscle is gastrocnemius, soleus, tibialis anterior muscle, or a combination thereof. Brookheart does teach muscle specific S1P knockout mice wherein S1P mRNA levels are reduced in the gastrocnemius of said mice (see paragraph 0138).
Regarding claim 20, Brookheart does not teach where the subject is greater than 60 years of age.
Regarding claim 3, Schiaffino teaches a review on the fiber types in mammalian skeletal muscles. Schiaffino teaches mammalian skeletal muscle comprises different fiber types where there are fast-twitch muscles, characterized by glycolytic metabolism, and slow-twitch muscles, rich in myoglobin and oxidative enzymes (see section titled ‘Four Major Fiber Types With Distinct Myosin Composition’).
Regarding claim 5, Moyer teaches where inhibition of myostatin and TGF-β1 signaling consistently leads to a significant reduction in the expression of MSS51 (see abstract).
Regarding claim 5, Wang teaches where SREBP-1 is a novel mediator of TGFβ1 signaling where SREBP-1 is dependent on a two-step cleavage process involving site-1 protease (see section titled TGFβ1-induced SREBP-1 activation requires SCAP, serine proteases, and PI3K signaling). Wang further teaches Fig. 2B which describes inhibition of SREBP-1 activation by fatostatin, and further shows inhibition by the S1P inhibitor AEBSF. Fig 2B of Wang shows where the administration of S1P inhibitor AEBSF leads to a decrease of SREBP transcriptional activity.
Regarding claim 16, Schiaffino teaches where rat skeletal muscles comprise of red muscle (red gastrocnemius) and white muscles (white gastrocnemius) (see section 3, paragraph C). Therefore, Schiaffino teaches where the gastrocnemius is part of the skeletal muscle system.
Regarding claim 20, Cohen teaches muscle wasting occurs systemically in older people (a condition known as sarcopenia) and where exercise is the only accepted approach to prevent or slow atrophy (see abstract).
It would have been obvious to one skilled in the art, before the effective filing date, to combine the teachings of Brookheart, Schiaffino, and Cohen, to arrive at a method for improving mitochondrial function in skeletal muscle in a subject in need thereof by inhibiting S1P in the skeletal muscle of a subject, where the skeletal muscle comprises glycolytic muscle fibers.
One would expect a reasonable chance of success as Brookheart already teaches enhanced mitochondrial metabolism is associated with S1P inhibition through a genetic construct or small molecule inhibitor. Brookheart observes S1P mRNA levels are decreased in S1P knockout mice in the gastrocnemius, which is classified as fast-twitch glycolytic muscle fibers evidenced by Schiaffino and wherein only some of the subjects of the embodiments have a S1P mutation. Furthermore, the combined teachings of Wang and Moyer clearly lay out the pathway where S1P regulates SREBP-1 which regulates TGF-β1 which regulates MSS51. Therefore, one would expect where a S1P inhibitor would inhibit SREBP1, which inhibits TGF-β1, which Moyer discloses TGF-β1 inhibition leads to a significant reduction of MSS51 expression.
One would be motivated to do so as Cohen teaches muscle wasting occurs systematically in older people, which is known as sarcopenia, and where exercise is the only accepted approach to prevent or slow atrophy. Though Cohen does not establish what age sarcopenia typically occurs, one would be motivated to administer the composition taught by Brookheart to a subject that is older than 60 years of age, in order to increase the capability to exercise, which is taught by Brookheart, to slow muscle atrophy, which is described in Cohen.
In view of the foregoing, claims 3, 6, 7, 16-21 are rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
Response to Arguments
Applicant’s arguments filed on 5/8/2026 have been fully considered but they are not persuasive. Regarding claim 3, applicant argues that Brookheart reference “does not teach a method of improving mitochondrial function where the skeletal muscle comprises glycolytic muscle fibers and wherein the method results in reduced MSS51 expression”. Applicant further argues that the specification establishes, for the first time, that S1P inhibition 1) increases mitochondrial respiration specifically in glycolytic (white) muscle fibers, but not in oxidative (red) muscle fibers), 2) reduces MSS51 expression in gastrocnemius, but not the soles, and produces increased muscle mass in specifically aged mice. Applicant argues the fiber-type specificity is a novel discovery not taught or suggest by the prior art. Applicant also argues that “MSS51 is inherently part of the same pathway that regulates muscle growth” conflates pathway membership with therapeutic predictability which are two distinct concepts. Mere knowledge that the gene exist in a common pathway does not provide reasonable expectation that targeting one upstream component will produce specific downstream therapeutic effect in a specific tissue type.
Examiner argues the basis of the rejection is dependent on the claims, not what is disclosed in the specification. Therefore, as claim 3 is currently written, applicant is claiming a method for improving mitochondrial function in skeletal muscle of a subject through an inhibitor (which is taught by Brookheart), wherein the skeletal muscle comprises glycolytic muscle fibers (taught by Schiaffino), and wherein the mitochondrial function in the skeletal muscle of the subject is improved (taught by Brookheart). The instant claim is interpreted as S1P inhibition increases mitochondrial function in any skeletal muscle, and that the skeletal muscle merely comprises glycolytic fibers, which is evidenced by Schiaffino. If applicant stands by the novelty of the present invention to increase mitochondrial respiration specifically in glycolytic muscle fibers, claim 3 should be amended to reflect said limitation such as “wherein the skeletal muscle comprises glycolytic muscle fibers and mitochondrial function of the glycolytic muscle fibers is improved”.
Regarding claim 3 and dependent claims, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Furthermore, in the instant action, examiner argues that the teachings of Moyer and Wang discloses that a S1P inhibitor would reduce SREBP-1 expression (see Fig. 2B of Wang), which further inhibits TGF-β1 as SREBP-1 is a mediator of TGF-β1. TGF-β1 inhibition has a clear inhibitory effect on MSS51 as taught by Moyer. Therefore, the combined arts of Moyer and Wang clearly suggest a S1P inhibitor would reduce MSS51 expression. With regards to the argument that the common pathway does not provide a reasonable expectation that targeting one upstream component will produce a specific downstream therapeutic effect, claim 3 is merely directed to improving mitochondrial function in the skeletal muscle of a broad range of subjects, wherein the skeletal muscle comprises glycolytic fibers (as it is well known in the art). Claim 5 only recites where MSS51 expression is reduced but does not specify where the reduction is in the skeletal muscle of a subject or in glycolytic muscle fibers. Therefore, these claims are directed to no therapeutic effect. As it stands, applicant does not indicate that mitochondrial respiration is increased specifically in glycolytic (white) muscle fibers or where MSS51 expression is reduced specifically in the gastrocnemius.
Regarding claim 21, applicant argues that the Brookheart reference is directed specifically to treating subjects with a site-1 protease mutation and all claims in Brookheart ‘032 require the subject to have “a S1P mutation”.
Examiner disagrees with this assessment. In Brookheart, the independent claim 1 broadly asserts a method of improving exercise tolerance or enhancing exercise performance in a subject. Furthermore, Brookheart teaches in some embodiments, the subject has a mutation in the S1P transmembrane (see paragraph 0012). Furthermore, Brookheart teaches Fig. 14 which tests WT mice with a S1P small molecule inhibitor with regards to exercise endurance against WT littermates without said S1P inhibitor.
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.
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Claims 1-3, and 6, 10-15, 17-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6, and 8 of U.S. Patent No. 11534423B2 in view of Brookheart et al. (US 2020/0215032 A1, published 7/9/2020) in view of Graham et al. (Mechanisms of exercise as a preventative measure to muscle wasting, Am. J. Physiol. Cell Physiol., Volume 321, Issue 1, published May 5, 2021), Cohen et al. (Muscle wasting in disease: molecular mechanisms and promising therapies, Nature Reviews Drug Discovery, Volume 14, pgs. 58-74, published 2015) and Schiaffino et al. (Fiber Types in Mammalian Skeletal Muscles, Physiological Reviews, Volume 91, Issue 4, published 2011).
Regarding claims 1, 3, 6, and 8 of the issued patent, claim 1 of the patent reads on a method of improving exercise tolerance or enhancing exercise performance in a subject comprising of administering a pharmaceutical composition comprising an effective amount to reduce or deplete S1P levels or reduce or deplete S1P activity in the subject, wherein the subject has a mutation in a gene encoding S1P. Claim 1-3 of the instant application consists of the same method (administering a S1P inhibitor to a subject in need thereof), wherein the broadness of a subject in need thereof can read on a subject with a S1P mutation. With the guidance of Brookheart and Graham, exercise endurance and performance is a result of mitochondrial enhancement derived from S1P inhibition as disclosed by Brookheart and that exercise is a very well known as a treatment for muscle wasting diseases or improving muscle mass, as taught by Graham. Therefore, the administration of a S1P inhibitor in the issued patent would inherently lead to the downstream therapeutic effects, such as increasing muscle mass or treating muscle wasting disease, of the claimed instant invention. Though claim 3 recites glycolytic muscle fibers, applicant only recites where the skeletal muscle comprises glycolytic muscle fibers, which is obvious as evidenced by Schiaffino.
Furthermore, the subject of interest overlaps as claim 6 of the issued patent recites the subject has cardiovascular diseases, dysfunctional muscle, etc. Cohen teaches that heart failure can lead to muscle loss known as cachexia, and dysfunctional muscle broadly reads on recited disease or conditions such as DMD and sarcopenia, or age related muscle loss. Therefore, the subject limitations presented in claims 10-15, and 20 would have been obvious in view of the art.
Claim 17-19 are directly recited as subjects in the issued patent (see claim 8).
Response to Arguments
Applicant’s arguments filed on 5/8/2026 have been fully considered but they are not persuasive. Applicant argues that the claims are directed to completely different methods and where the instant claims are directed to completely different populations where nothing in the instant application would have suggested that the methods for increasing skeletal muscle mass, treating muscle wasting, or improving mitochondrial function in glycolytic muscle fibers would have been effective at improving exercise tolerance or treating the diseases of the ‘423 patients.
Examiner disagrees as the instant claims, as written, are not directed towards increasing mitochondrial function of the glycolytic muscle fibers in a subject, only that skeletal muscles comprised glycolytic fibers (claim 3), which is rendered obvious by Schiaffino. With regards to the patient populations, the instant claim 1-3 only recite a subject in need thereof, not any specific mutations present or not present. Therefore, a patient with a mutation in S1P that may or may not have a disease where one exhibits dysfunctional muscles clearly reads on a patient in need thereof, as recited in the instant claims. Brookheart further provides evidence that you would administer an S1P inhibitor directly to the skeletal muscle of a subject, and Graham teaches where exercise is directly linked to an increase of muscle mass or prevention of muscle atrophy.
Conclusion
No claims are allowed.
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/D.T.Y./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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