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 .
Claims 1 and 98-100 are pending.
Status of the Application
Applicant’s response and amendment filed 11 September 2026 are acknowledged and entered.
Applicant has amended Claim 1. Applicant has added Claims 98-100. Applicant has cancelled Claims 3, 6, 8, 40, 42, 45, 49, and 90-97.
Applicant has amended the Drawings and Spec. to overcome objections; the objections are withdrawn.
Applicant has amended Claim 1 to overcome the claim objections; the objections to the claims are withdrawn.
Applicant has amended Claim 1 to overcome the 112(a) rejection; the 112(a) rejection maintained and updated in response to the claim amendments.
Applicant has amended Claim 1 to overcome the 102 and 103 rejections; the 102 rejection is withdrawn but the 103 rejection is maintained and updated in response to the claim amendments.
Applicant has amended Claim 1 to overcome the NSDP rejections; all the NSDP rejections are withdrawn in view of the claim amendments.
Claims 1 and 98-100 are examined.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
Claim Interpretation
The claims recite myofibers. The Spec. indicates (p.28 L10-13) myofibers are simply muscle cells.
The Spec. does not define muscle fiber hypertrophy. However, WO269 (of record) teaches (p. 19 L9-20):
the expression « skeletal muscle hypertrophy » refers to a gain of skeletal muscle mass characterized by an increase in the size of pre-existing myofibers and/or an increase in the number of myofibers and/or an increase in the mean number of nuclei per myotube and/or an increase in the fusion index (number of nuclei in myotubes divided by total number of nuclei in myoblasts and myotubes).
Since that is an art-recognized definition, the claims interpret the term muscle fiber hypertrophy according to that definition.
Claim Rejections - 35 USC § 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 1 and 98-100 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. This is a written description rejection. This rejection is maintained and updated in response to the amendments.
Claim 1 recites a method of increasing muscle fiber hypertrophy in a subject, the method comprising administering to muscle fibers of the subject an RNAi molecule specifically targeting RNA encoding ALK4 and an RNAi molecule specifically targeting RNA encoding ALK5 signaling in myofibers of the subject, such that muscle fiber hypertrophy is induced in the subject. Claims 98-100 recite the method wherein each RNAi molecule is an siRNA (Claim 98), and shRNA (Claim 99), or a miRNA (Claim 100).
The broad claims encompass the large genera of RNAi molecules that inhibit ALK4 and ALK5 (i.e., Claims 1 and claim depending therefrom) and the large subgenera of shRNA/siRNA/miRNA agents that inhibit ALK4 and ALK5 (i.e., Claims 98-100). Any kind of shRNA(s)/siRNA(s)/miRNA(s) that inhibits ALK4 and ALK5 would be encompassed by the claims as instantly presented.
There is a written description problem because Applicant has not disclosed any physical structure that is responsible for the recited inhibiting ALK4 and ALK5 such that muscle fiber hypertrophy is induced. Although Claims 98-100 recite that the shRNA/siRNA/miRNA RNAi molecules specifically target RNA encoding ALK4/ALK5, such RNAi molecules encompass large and diverse subgenera of diverse physical structures.
An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163.
The Spec. describes that (p. 3 L29-34) agents that specifically inhibit ALK4/ALK5, including nuclease-based gene editing molecules, ASO/shRNA/siRNA/miRNA; (p. 27 L18-24) agents that inhibit (e.g., specifically inhibit) signaling through ALK5 and ACVR2… an ACVR2/ALK5 hybrid decoy receptor, and a peptide or small molecule inhibitors capable of disrupting the ACVR2-ALK5 interaction. The Spec. also describes (pp. 27-38 L25-L10) the myostatin signaling pathway, broad categories of inhibitory agents, and players in the myostatin signaling pathway that may be inhibited. Those lists are inadequate to meet the statutory written description requirement because none of those passages discusses specific physical structures suitable to inhibit ALK4/ALK5 signaling such that muscle fiber hypertrophy is induced in any way that demonstrates that Applicant was in possession of the full scope of the claimed method.
Regarding what structure is encompassed by the RNAi molecules that specifically target ALK4 and ALK5 such that muscle fiber hypertrophy is induced, the Spec. does not provide information describing their features. The Spec. does not disclose what physical structure responsible for the claimed function.
Applicant’s examples discuss (starts on p. 49 L30; pp. 60-61 L31-8) using mice carrying floxed alleles for Acvr2, Acvr2b, Alk5, TGFβRII, Cfc1b, Mstn, and ALK4. However, those examples are not sufficient to provide written description support for large genus of RNAi molecules that specifically target RNA encoding ALK4/ALK5 such that muscle fiber hypertrophy is induced and the large subgenera of shRNA/siRNA/miRNA agents that inhibit ALK4 and ALK5. Floxed alleles are not agents that can be administered to a subject. Although the claims claim the functional characteristics (i.e., specifically inhibiting ALK4- and ALK5-encoding RNA using RNAi molecules specifically target RNA encoding ALK4/ALK5 and inhibiting ALK4/ALK5 signaling by using shRNA/siRNA/miRNA agents to target RNA encoding ALK4/ALK5, such that muscle fiber hypertrophy is induced), the functional characteristic is not coupled with any known structure.
Although the Specification teaches the examples discussed above, it does not identify a core structure necessary for performing the claimed function(s) of specifically targeting RNA encoding ALK4/ALK5 by using RNAi molecules or being shRNA/siRNA/miRNA molecules that specifically target RNA encoding ALK4/ALK5, such that muscle fiber hypertrophy is induced. The claims and Spec. do not identify any core structures necessary for specifically targeting RNA encoding ALK4 and specifically inhibiting RNA encoding ALK5 that result in induction of muscle fiber hypertrophy. The Spec. does not disclose any core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for specifically inhibiting RNA encoding ALK4 and ALK5 (whether the RNAi molecule is any sort of RNAi molecule or specifically a shRNA/siRNA/miRNA) in such a way to demonstrate possession of the full invention as claimed at time of filing. The floxed alleles for Acvr2, Acvr2b, Alk5, TGFβRII, Cfc1b, Mstn, and ALK4 do not share a core structure, and those floxed alleles are not agents that can be administered to a subject.
The specification teaches only these species within the claimed genus/subgenera (floxed alleles for Acvr2, Acvr2b, Alk5, TGFβRII, Cfc1b, Mstn, and ALK4) but those are only a paltry number compared with the breadth of what is claimed—any RNAi molecule that specifically targets ALK4 and any RNAi that specifically targets ALK5, including any shRNA/siRNA/miRNA that inhibit, in any manner, ALK4 RNA and ALK5 RNA with the required outcome of inducing muscle fiber hypertrophy. Altogether, the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genus and subgenera that are encompassed by the claims: any RNAi molecule that specifically targets RNA encoding ALK4 and any RNAi that specifically targets RNA encoding ALK5, including any shRNA/siRNA/miRNA that inhibit, in any manner, ALK4 and ALK5 such that muscle fiber hypertrophy is induced . Nothing in the Spec. discloses what physical structure of ALK4/ALK5 inhibiting RNAi molecules is responsible for inducing muscle fiber hypertrophy.
While none of these elements is specifically required to demonstrate possession, in combination their absence means that one skilled in the art at the time of filing would conclude that the inventors lacked possession of the full breadth of the invention claimed. Claims 1 and 98-100 are rejected for failing to demonstrate possession of the claimed invention. Claims 98-100 are rejected because they depend from Claim 1 and do not remedy the issues.
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.
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) 1 and 98-100 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2006/025988 (published 09 March 2006, “WO988”, of record) as evidenced by Han (and Mitch 2011. Author Manuscript of: Targeting the Myostatin Signaling Pathway to Treat Muscle Wasting Diseases. Curr. Opin. Support Palliat. Care 5[4]: 334–341, “Han”, of record on IDS), and in view of International Publication Number WO 2019/180269 (published 26 September 2019, “WO269”, of record on IDS), Hu (et al. June 2020. Therapeutic siRNA: state of the art. Signal Transduct. Target. Ther. 5:101, “Hu”, of record), and NCBI (Homo sapiens activin A receptor type 1B [ACVR1B], transcript variant 1, mRNA. version archived 02 May 2019. Accessed 08 June 2026, “NCBI”, of record). This rejection is maintained and updated in response to the claim amendments.
All citations to WO document p. #s refer to PDF p. #.
WO988 is drawn to using ALK5 inhibitors to inhibit myostatin signaling and thereby increase lean muscle mass in animals.
Regarding Claim 1: WO988 discloses (p. 4 L12-18) an ALK5/ALK4 dual inhibitor that increases muscle mass in animals. WO988 discloses (p. 6 L8-11) administration of the inhibitor results in decreased fat tissue. WO988 teaches (p. 7 L8-11) that although the[ir] invention is not bound by any particular theory, it is suggested that the desirable effects observed when ALK5 and/or ALK4 receptor inhibitors are administered to animals, the increase in muscle mass is due, at least in part, to inhibition of the Ser/Thr kinase activity associated with ALK5. That indicates that inhibiting ALK4 and ALK5 produces desirable effects. WO988 teaches (p. 15 L6-19) their invention can be used in food producing animals, companion animals, and/or humans.
Regarding inhibition in myofibers, WO988 teaches (p. 16 L9-17; p. 20 L16-17) their compounds inhibit signaling through the ALK4 and ALK5 receptors.
Further regarding inhibition in myofibers, Han provides evidence that (Fig. 2) ALK4/ALK5 signaling occurs in muscle. That indicates that inhibition of ALK4/ALK5 occurs in myofibers/muscle cells. An excerpt of Fig. 2 is shown here:
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Regarding Claim 1, WO988 indicates that inhibiting ALK4/ALK5 increases muscle mass.
WO988 teaches (pp. 15-16 L20-9) treatment with their methods of inhibiting ALK4/ALK5 results in gains in muscle deposition of at least about 5%. Gains in muscle deposition would occur in all muscles, including the specific muscles: tricep, quadricep, and gastrocnemius/plantaris.
WO988 teaches (pp. 4-5 L13-15) small molecule inhibitors.
WO988 as evidenced by Han teaches inhibiting ALK4 and ALK5 signaling in muscle cells to increase muscle weight and reduce body fat content. WO988 as evidenced by Han teaches their method increases muscle weight by at least 5% compared to a control or baseline. Those teachings would have motivated an artisan to inhibit ALK4 and ALK5 in muscle cells in increase muscle mass.
WO988 as evidenced by Han does not explicitly discuss using antisense or RNA interference (RNAi) agents to target ALK4/ALK5 expression and thereby inhibit ALK4/ALK5.
However, WO269 discloses (pp. 7-13 L30-10) ALK5 inhibitors that (§Abstract) induce skeletal muscle hypertrophy. WO629 teaches (p. 19 L9-20):
the expression « skeletal muscle hypertrophy » refers to a gain of skeletal muscle mass characterized by an increase in the size of pre-existing myofibers and/or an increase in the number of myofibers and/or an increase in the mean number of nuclei per myotube and/or an increase in the fusion index (number of nuclei in myotubes divided by total number of nuclei in myoblasts and myotubes).
Therefore, an artisan would understand that WO988’s methods of inhibiting ALK4 and ALK5 to increase muscle mass would inherently read on the outcome of inducing muscle fiber hypertrophy.
WO629 teaches (p. 41 L6-10) their ALK5 inhibitors induce significant muscle hypertrophy. WO269 teaches (p. 9 L1-13) single-stranded antisense molecules, shRNA molecules, siRNA molecules, and miRNA molecules, which specifically reduce or suppress expression of ALK5 and thereby reduce or suppress expression of ALK5 protein.
Regarding the limitation of Claim 1 administering to muscle fibers of a subject: WO269 teaches (p. 16 L10-20) administering pharmaceutical compositions via intramuscular administration.
WO269 doesn’t teach ASO/shRNA/siRNA/miRNA that targets ALK4.
However, Hu, drawn to a review about nucleic acid therapies, teaches (§Introduction ¶1-4) gene therapy is a promising therapeutic platform because it enables precise and personalized disease treatment. Hu teaches (same §, ¶4):
siRNA has innate advantages over small molecular therapeutics and monoclonal antibody drugs because siRNA executes its function by complete Watson–Crick base pairing with mRNA, whereas small molecule and monoclonal antibody drugs need to recognize the complicated spatial conformation of certain proteins… [A]ny gene of interest can be targeted by siRNA since only the right nucleotide sequence along the targeting mRNA needs to be selected. This advantage confers the siRNA modality with a shorter research and development span and a wider therapeutic area than small molecule or antibody drugs.
Hu further teaches (§Abstract, §Conclusions ¶2) siRNA therapy can be administered quarterly or twice-yearly, an infrequency of administration that had never been realized in the history of pharmaceuticals. An artisan would have readily recognized that those advantages apply to any nucleic acid–based drug because ASOs, siRNA, shRNA, and miRNA all operate by base-pairing to their mRNA target.
Hu teaches (§Introduction ¶5-6) chemical modifications that allow an siRNA to overcome disadvantages of nucleic acid–based therapies.
Hu’s teachings indicate that it was well within the ability of a person of ordinary skill to design nucleic acid therapy for any target, as long as the target sequence was known.
As discussed above, WO269 teaches ALK5-targeting nucleic acid–based therapies to inhibit ALK5 expression but not ALK4-targeting nucleic acid–based therapies.
However, NCBI demonstrates that the sequence of ALK4 was known. Note that the NCBI document refers to “ACVR1B”; the abbreviation “ACVR1B” is simply a different abbreviation for “ALK4”.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify WO988’s method of increasing muscle weight and reducing body fat by inhibiting ALK4 and ALK5 signaling with WO269’s ALK5-targeting nucleic acid–based therapy, Hu’s teachings about the benefits of nucleic acid–based therapies over small molecule or antibody therapies, and NCBI’s ALK4-encoding mRNA sequence. One would have done so for the benefits of rapidly producing nucleic acid inhibitors that specifically inhibit both ALK4 and ALK5 and using them to increase muscle deposition (as taught by WO988), thereby increasing muscle fiber hypertrophy. One would have been motivated to do so with a reasonable expectation of success because Hu teaches benefits of nucleic acid–based therapies for targeting any gene (i.e., such therapies are specific, have a short research/development timeline, and their effects persist a long time in the body) and Hu’s teachings indicate it was well within the capability of a person of ordinary skill to design a nucleic acid–based therapy to target any gene of interest, as long as its sequence was known. NCBI demonstrates the ALK4-encoding mRNA sequence was known. A person of ordinary skill would have wanted to use separate ALK4 and ALK5 nucleic acid–based inhibitors because separate inhibitors are more specific than dual inhibitors and Hu teaches nucleic acid–based inhibitors that have high activity, high affinity, high specificity, (§Abstract) are longer-lasting, and are easier to design than small molecule inhibitors.
Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). The motivation to combine falls under an “obvious to try” rationale; see MPEP 2143(I)(E):
To reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
(1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense.
Regarding (1): WO988 demonstrates there was a need in the art for therapies that increase muscle weight and muscle fiber hypertrophy by inhibiting both ALK4 and ALK5. WO269 clearly demonstrates nucleic acid–based therapies for targeting (and inhibiting) mRNA encoding ALK5 were envisioned. Hu indicates that highly specific and long-acting medications were greatly desired in the art, but that small molecule therapies (such as the dual ALK4/ALK5 small molecule inhibitor of WO988) do not produce effects that are as long-lasting as RNAi molecule-based therapies. That indicates there was a market pressure to produce an RNAi molecule-based therapy to inhibit ALK4 and ALK5.
Regarding (2): WO988 teaches inhibiting only two proteins: ALK4 and ALK5 has the desired outcome of increasing muscle mass. WO269 discloses nucleic acid–based therapies that target ALK5. NCBI demonstrates the sequence of ALK4-encoding mRNA was known and available.
Regarding (3): Hu’s teachings indicate it was routine and conventional to use nucleic acid–based therapies to target any gene of interest and that such targeting occurs when an oligont base-pairs to its target mRNA.
Since WO988 teaches inhibiting ALK4 and ALK5 to increase muscle deposition, WO269 teaches oligont that target ALK5 and using them to induce muscle regeneration, and Hu and NCBI indicate that all of the elements necessary to produce ALK4-targeting oligont were known, a person of ordinary skill in the art would have found it obvious to produce an RNAi-based method of inhibiting ALK4 and ALK5 by administering oligont that inhibit each of ALK4 and ALK5. One would have been motivated to do so because WO988 teaches inhibiting both targets to increase muscle weight, and one would have had a reasonable expectation of success in doing so because WO269 and Hu indicate designing and using such treatment was routine and conventional, and because NCBI provides an ALK4 mRNA target sequence. The teachings of Hu and WO269 indicate that siRNA, shRNA, and miRNA are all representative molecules used to trigger gene inhibition.
Therefore, Claims 1 and 98-100 would have been obvious in view of WO988, WO269, Hu, and NCBI.
Claim(s) 1 and 98-100 are rejected under 35 U.S.C. 103 as being unpatentable over WO988 as evidenced by Han, and further in view of International Publication Number International Publication Number WO 2008/005002 (published 10 January 2008, “WO002”, of record) and Hu (cited above, of record). This rejection is maintained and updated in view of the claim amendments.
All citations to WO document p. #s refer to PDF p. #.
WO988 is drawn to using ALK5 inhibitors to inhibit myostatin signaling and thereby increase lean muscle mass in animals.
Regarding Claim 1: WO988 discloses (p. 4 L12-18) an ALK5/ALK4 dual inhibitor that increases muscle mass in animals. WO988 discloses (p. 6 L8-11) administration of the inhibitor results in decreased fat tissue. WO988 teaches (p. 7 L8-11) that although the[ir] invention is not bound by any particular theory, it is suggested that the desirable effects observed when ALK5 and/or ALK4 receptor inhibitors are administered to animals, the increase in muscle mass is due, at least in part, to inhibition of the Ser/Thr kinase activity associated with ALK5. That indicates that inhibiting ALK4 and ALK5 produces desirable effects. WO988 teaches (p. 15 L6-19) their invention can be used in food producing animals, companion animals, and/or humans.
Regarding inhibition in myofibers, WO988 teaches (p. 16 L9-17; p. 20 L16-17) their compounds inhibit signaling through the ALK4 and ALK5 receptors.
Further regarding inhibition in myofibers, Han provides evidence that (Fig. 2) ALK4/ALK5 signaling occurs in muscle. That indicates that inhibition of ALK4/ALK5 occurs in myofibers/muscle cells. An excerpt of Fig. 2 is shown here:
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Regarding Claim 1, WO988 indicates that inhibiting ALK4/ALK5 increases muscle mass.
WO988 teaches (pp. 15-16 L20-9) treatment with their methods of inhibiting ALK4/ALK5 results in gains in muscle deposition of at least about 5%. Gains in muscle deposition would occur in all muscles, including the specific muscles: tricep, quadricep, and gastrocnemius/plantaris. As explained above in §Claim interpretation, those teachings read on methods of increasing muscle fiber hypertrophy.
WO988 teaches (pp. 4-5 L13-15) small molecule inhibitors.
WO988 as evidenced by Han teaches inhibiting ALK4 and ALK5 signaling in muscle cells to increase muscle weight and reduce body fat content. WO988 as evidenced by Han teaches their method increases muscle weight by at least 5% compared to a control or baseline. Those teachings would have motivated an artisan to inhibit ALK4 and ALK5 in muscle cells in increase muscle mass.
WO988 as evidenced by Han does not explicitly discuss using RNA interference (RNAi) agents to target ALK4/ALK5 expression and thereby inhibit ALK4/ALK5.
However, teachings of WO002, drawn to oligonucleotides (oligont) that target the myostatin signaling pathway, would have made it obvious to modify the method of WO988 by using RNAi molecule inhibitors instead of small molecule inhibitors.
WO002 discloses (§Abstract) oligont that target genes involved in muscle wasting and/or muscle growth. WO002 discloses (p. 2 L1-15) their invention can treat various muscle wasting conditions. WO002 discloses (p. 2 L15-18) their invention promotes muscle growth.
WO002 teaches (p. 2 L1-20) muscle wasting conditions replace healthy muscle with fibrous and fatty tissues but their invention provides methods for treating muscle wasting conditions and promoting muscle growth by administering oligont compositions. As explained above in §Claim interpretation, those teachings read on methods of increasing muscle fiber hypertrophy.
WO002 discloses (p. 4 L17-20) embodiments wherein their invention provides an RNAi that modulates expression of myostatin or a myostatin receptor [emphasis added]. Regarding what they mean by myostatin receptor, WO002 discloses (p. 34 L16-20) receptors ALK4 and ALK5 form a heteromeric complex with myostatin that leads to phosphorylation of Smad and thereby mediates the effects of myostatin. That passage clearly indicates that not only are ALK4/ALK5 required for myostatin signaling, but WO002 considers ALK4 and ALK4 myostatin receptors. Taken together, the whole teachings of WO002 disclose a method of increasing muscle weight by inhibiting ALK4/ALK5 signaling.
WO002 teaches (p. 16 L10-35) RNAi is good to use for treating muscle wasting diseases because its effects persist for multiple cell divisions and it is extremely powerful and specific. WO002 teaches (p. 2 L1-5, p. 24 L20-30) RNAi molecules including siRNA.
WO002 teaches (p. 25 L1-11) various kinds of administration, including parenteral, and teaches a person of ordinary skill in the art can determine an appropriate mode of administration.
As discussed above, since myostatin signaling requires ALK4/ALK5, it would have been obvious to a person of ordinary skill to try inhibiting any component of the myostatin signaling pathway to increase muscle mass.
WO988 and WO002 do not explicitly teach RNAi that is miRNA or shRNA.
However, Hu teaches (§Introduction ¶1-4) RNAi therapy is a promising therapeutic platform because it enables precise and personalized disease treatment. Hu teaches (same §, ¶4):
siRNA has innate advantages over small molecular therapeutics and monoclonal antibody drugs because siRNA executes its function by complete Watson–Crick base pairing with mRNA, whereas small molecule and monoclonal antibody drugs need to recognize the complicated spatial conformation of certain proteins… [A]ny gene of interest can be targeted by siRNA since only the right nucleotide sequence along the targeting mRNA needs to be selected. This advantage confers the siRNA modality with a shorter research and development span and a wider therapeutic area than small molecule or antibody drugs.
Hu further teaches (§Abstract, §Conclusions ¶2) siRNA therapy can be administered quarterly or twice-yearly, an infrequency of administration that had never been realized in the history of pharmaceuticals. An artisan would have readily recognized that those advantages apply to any nucleic acid–based drug because ASOs, siRNA, shRNA, and miRNA all operate by base-pairing to their mRNA target.
Hu teaches (§Introduction ¶1-2, Figs. 1, 3, and 5g) siRNA, miRNA, and shRNA. Hu teaches (same §) siRNA and miRNA have different roles in pharmaceutical practice because siRNA is more efficient and specific than miRNA, but miRNA can inhibit several different target genes simultaneously. That would have motivated an artisan to determine whether using two single siRNA or shRNA, each targeting ALK4 or ALK5 was more or less effective than using one miRNA that is able to target both ALK4 and ALK5 from a single miRNA molecule.
Regarding the limitation of Claim 1 that the method comprises administering RNAi to muscle fibers of a subject, Hu teaches (§SiRNA modification ¶1) RNAi molecules that medicate gene silencing in vivo, especially in tissues that receive local administration of the drug. That would have motivated an artisan to administer any RNAi agent to the tissue where its effects are desired.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify WO988’s method of increasing muscle weight and reducing body fat by inhibiting ALK4 and ALK5 signaling with WO002’s teachings about myostatin signaling, about ALK4/ALK5 role in myostatin signaling, and about blocking myostatin signaling (including inhibiting a myostatin receptor) using RNAi to treat muscle wasting, and with Hu’s teachings about the uses of the different kinds of RNAi. One would have done so for the benefits of treating muscle wasting and inducing muscle fiber hypertrophy. One would have done so for the benefits of providing long-lasting treatment effects and testing which of the different modalities is best suited for inhibiting both ALK4 and ALK5 to treat muscle wasting.
A person of ordinary skill would have understood, since WO002 teaches (cited above) that myostatin signaling requires formation of a heteromeric complex with ALK4/ALK5, that myostatin signaling could be inhibited by blocking any of those players or any player in the myostatin signaling pathway, including ALK4/ALK5. One would have been motivated to use WO988 and WO002’s method of inhibiting ALK4 and ALK5 signaling to treat muscle wasting with a reasonable expectation of success because WO988 teaches (p. 30 L16-17) inhibiting ALK4 and/or ALK5 increases lean muscle tissue and because WO002 teaches (p. 4 L17-18) their invention encompasses inhibiting myostatin or a myostatin receptor, (p. 34 L16-19) names ALK4 and ALK5 as those receptors, and teaches (p. 36 L7-31) inhibiting myostatin signaling to treat muscle wasting diseases. One would have been motivated to use WO002 and Hu’s oligont therapies because Hu teaches oligont can produce longer-lasting effects than small molecules. It would have been a simple matter to modify WO988’s method of inhibiting ALK4 and ALK5 to treat muscle wasting with the long-lasting and highly specific oligont ALK4- and ALK5-targeting therapies of WO002 and Hu, and doing so would have increased muscle fiber hypertrophy in a subject. It would have been obvious to an artisan to administer the oligont to the muscle of a subject because Hu teaches RNAi molecules that mediate gene silencing in vivo is especially effective in tissues that receive local administration. Therefore, all limitations of Claims 1 and 98-100 would have been obvious in view of the teachings of WO988, WO002, and Hu.
Response to Arguments
Applicant's arguments filed 11 September 2026 have been fully considered but they are not persuasive. Arguments that are no longer relevant are not addressed.
Written Description (WD) Rejections
The response to the WD rejections are not persuasive. Applicant argues (p. 6 full ¶2) the WD requirement may be satisfied by disclosure of structural or physical characteristics couple with a known correlation between structure and function and they don’t need to show “actual reduction of every species”. Applicant asserts that their Spec. discloses the target sequences to which their claimed RNAi molecule is directed, and that those disclosures are sufficient to meet the requirement. Applicant then refers to passages in the Spec. that generically describe how the RNAi mechanism works. Applicant refers to a passage that discusses using a flox/recombinase system to delete Exons 2 and 3 of ALK4. That passage also generically mentions a floxed ALK5 line. Applicant then reiterates that the (p. 7 full ¶2) floxed allele example is sufficient to demonstrate possession of the vast number of species encompassed by the method and they’re not required to reduce to practice every species.
Those arguments aren’t persuasive because, as mentioned in the rejection, what is shown doesn’t demonstrate possession of any RNAi molecules that induce muscle fiber hypertrophy. The arguments aren’t persuasive because floxed alleles aren’t agents and they can’t be administered to the muscle fibers of a subject. The claims recite a method comprising administering to the muscle fibers of a subject an RNAi molecule that specifically targets ALK4 RNA and an RNAi molecule that specifically targets ALK5 RNA, and that administrations of those molecules induce muscle fiber hypertrophy.
The Spec. discusses only (pp. 31-32 L30-35) the RNAi is complementary to a target sequence but has not demonstrated that any siRNA/shRNA/miRNA targeting any portion of those sequences would effectively bind their targets such that muscle hypertrophy is induce. Furthermore, those of ordinary skill in the art understand that the claimed RNAi molecules bind their mRNA target in the cytoplasm of the cell. That means that an artisan couldn’t reasonably predict that, for example, siRNAs designed to target any regions of the disclosed SEQ ID NOs would necessarily specifically target RNA encoding ALK4 and RNA encoding ALK5 such that muscle fiber hypertrophy is induced. Applicant hasn’t demonstrated that any siRNA/shRNA/miRNA would bind the claimed targes and result in the claimed outcome of inducing muscle fiber hypertrophy.
In response to Applicant’s assertion that (p. 6 full ¶2) they’ve disclosed the target sequences to which an RNAi molecule is directed (SEQ ID NOs 1 and 3), that isn’t persuasive because the Spec. discloses (pp. 37-39) all of the application’s nucleic acid SEQ ID NOs (none of which is claimed) are DNA sequences that are each longer than 4500-10000 bases. That does not demonstrate possession of even one RNAi molecule that targets RNA encoding ALK4 or RNA encoding ALK5 such that muscle fiber hypertrophy is induced in the subject, which is what is claimed. The Spec. doesn’t demonstrate that targeting any portion of the disclosed SEQ ID NOs would result in an RNAi molecule that specifically targets either intended target or results in inducing muscle fiber hypertrophy.
The floxed alleles used in the examples comprise but a single example of a structure that operates in a completely different way than an RNAi molecule that targets RNA encoding ALK4 and an RNAi molecule that targets RNA encoding ALK5. The Spec. itself discusses (pp. 50-51 L19-3) the ALK4 flox mouse line targeted exons 2-3 but the SEQ ID NOs Applicant has submitted (pp. 37-39) are all DNA sequences that are over 4500 bases long, comprise multiple exons besides exons 2-3, and do not exemplify any RNA molecules that are suitable RNAi molecules that target RNA encoding ALK4 and RNA encoding ALK5 such that muscle fiber hypertrophy is induced in the subject.
One example of a flox allele for each gene is not sufficient to demonstrate that Applicant was in possession of any RNAi molecules, let alone the entire genera of siRNAs, shRNA, and miRNAs that successfully target and interfere with ALK4 mRNA and ALK5 mRNA such that muscle fiber hypertrophy is induced. Furthermore, a discussion of the general mechanism by which RNAi generically works is not sufficient to demonstrate possession of the entire genera of RNAi molecule species encompassed by the claims, let alone that carrying out the method induces muscle fiber hypertrophy.
The rejection discusses that the claims and Spec. do not identify any core structures necessary for specifically targeting RNA encoding ALK4 and specifically inhibiting RNA encoding ALK5 wherein administering those RNAi molecules induces muscle fiber hypertrophy. The Spec. discloses (p. 32 L1-15) what it means for an oligont to be complementary to a target sequence and that binding of an antisense oligonucleotide to an mRNA target can interfere with normal cellular processing of the mRNA, and therefore expression of the encoded protein, through multiple mechanisms. The Spec. doesn’t disclose any RNAi molecules that work by any of the mechanisms described. The Spec. does not demonstrate that targeting any portion of RNA encoding ALK4 or targeting any portion of RNA encoding ALK5 would induce muscle fiber hypertrophy.
The WD rejection is maintained for those reasons.
103 Rejections
Applicant argues against the 103 rejection (§1A/B, pp. 9-11) because they assert (1) the rejection provides no motivation to substitute a nucleic acid-based inhibitor for the small molecule inhibitor of WO988 and (2) there would have been no reasonable expectation of success.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
Those arguments regarding (1, see §1A) aren’t found persuasive because Hu provides many reasons why an artisan would want to use nucleic acid-based therapies instead of a small molecule: RNAi is highly specific and longer-lasting than small molecules. Hu discusses (§Abstract, §Conclusions) RNAi-based therapies enable quarterly or twice-yearly administration which is an achievement that hasn’t been realized with any other sorts of pharmaceuticals. That provides a clear motivation for an artisan to modify the dual ALK4/ALK5 small molecule inhibitor of WO988 to an RNAi-based therapy instead: longevity.
Regarding Applicant’s arguments that no cited reference discloses even a single ALK4 inhibitor, and the references don’t supply a finite number of predictable therapeutics, that isn’t found persuasive for several reasons. First of all, WO002 provides (pp. 1-6, pp. 11-14, p. 16) a long discussion of how to produce and perfect RNAi compositions, including compositions that (p. 3 L30-35) target two myostatin receptors (which they teach, p. 34 L15-20, is a genus that includes ALK4 and ALK5). Part of that discussion (specifically pp. 11-14) talks about which portions of a target RNA to target (e.g., the 5’end, see p. 12 L15-20), how to use various computer programs to design and optimize an RNAi molecule, and appropriate GC content. Similarly, WO269 teaches (p. 9 L1-15) methods of designing, producing, and using RNAi molecules are well known by one of ordinary skill, and Hu describes (§Introduction, entire § and throughout) how to produce an RNAi molecule. Those teachings indicate that once a target sequence is known, it is obvious to produce specific RNAi molecules that inhibit that target and obvious how to go about doing so.
As explained, all of those teachings provide a clear motivation to use RNAi molecules instead of a small molecule inhibitor, and demonstrate doing so would have been well within the purview of a person of ordinary skill.
In addition, the arguments aren’t found persuasive because Applicant has already asserted in their response to the 112(a) rejection that all that is necessary to produce a functional RNAi molecule is a known target sequence, thereby acknowledging that NCBI provides enough information to produce a functional RNAi molecule. Unlike the Spec., however, the cited references provide much more information about how to produce a functional RNAi molecule. As discussed, WO002 teaches which end of the target RNA should be complemented by the oligont as well as providing tools for determining binding energy and disclosing requisite GC content.
The scope of the rejection is commensurate with the scope of the claims. The claims broadly recite using RNAi to specifically target RNA encoding ALK4 and RNA encoding ALK5, and that is what the combination of the references teaches. As stated, the combination of references goes even further because they teach what portion of the RNA target the oligont should complement and because Hu teaches (§Introduction ¶4) the importance of targeting the right nucleotide sequence along the mRNA, (§Modification patterns used in clinical studies or for commercial siRNA ¶4) iterative screening approach to improve an RNAi, and (§DPC or TRiM employed therapeutics ¶1) testing over 100 candidates to determine which elicit the greatest levels of target gene knockdown. If the claims recited specific RNAi sequences, the rejection would address those limitations. As it stands, the rejection addresses exactly what the claims recite. The references demonstrate it is routine and conventional in the art of RNAi molecule design to produce RNAi molecules by starting with the whole sequence and designing a large number of candidate RNAi molecules to test which have the best effects.
Therefore, Applicant’s arguments in §1 aren’t persuasive.
In §2, Applicant argues that the combined references do not provide a reasonable expectation of success. That is not found persuasive because WO988 teaches a dual ALK4/ALK5 inhibitor results in the claimed outcomes. Each of Hu, WO269, and WO002 teach that it is routine and conventional to produce RNAi molecules that bind a target having a known sequence. In response to Applicant’s argument that Hu doesn’t mention ALK4, that is not persuasive because Hu teaches (§Abstract) it is theoretically possible to silence any gene in a sequence-specific manner by using RNAi. Hu teaches (cited above) the process for producing RNAi is iterative and it is routine and conventional to test a large number of candidates. WO002 teaches instructions for making RNAi that inhibit myostatin receptors and specifically indicates ALK4 and ALK5 are two such receptors.
Regarding Applicant’s arguments about unpredictability because their Spec. cites a study wherein inhibiting only ALK4 has the opposite effect as that claimed, those aren’t found persuasive because the example discussed in the Spec. demonstrates only that the effects of a single ALK4 inhibitor are unpredictable. Meanwhile, the rejection states that WO988 teaches dual ALK4/ALK5 inhibitors. Furthermore, an artisan wouldn’t have found that study cited in the Spec. relevant because WO988 teaches (p. 4 L11-23) a small molecule inhibitor that inhibits ALK5 and ALK4 produces the increase in muscle mass and their inhibitor specifically inhibits the ALK5 receptor and the ALK4 receptor [emphasis added]. They would have been motivated to produce RNAi molecules that inhibit both ALK4 and ALK5. The combination of references makes obvious a method of inhibiting two targets, not one target, and certainly not only ALK4. WO988 (cited), WO269 (see p. 25 L6-10 and L18), and WO002 (cited) all teach inventions that include or can include inhibiting multiple targets. WO988 teaches a dual ALK4/ALK5 inhibitor produces the desirable outcome, and Hu teaches RNAi molecules provide various benefits including high specificity and longevity of action. Regarding Applicant’s arguments that Hu says nothing about whether the resulting molecule will produce the desired physiological effect, that is not persuasive because Hu was cited to demonstrate that RNAi molecules can have better effects than small molecules and it is routine and conventional to produce RNAi molecules for any target. Altogether, the cited references provide a motivation to combine and a reasonable expectation of success. Guaranteed success is not a requirement of 103. Applicant’s arguments in §1B are not persuasive for those reasons.
Regarding Applicant’s argument (§III) that WO002 names ALK4 and ALK5 only once in a single sentence and WO002 doesn’t show example of inhibiting ALK4/ALK5, those arguments aren’t persuasive because WO002 mentions repeatedly that (p. 3 L25-30, p. 4 L10-35, pp. 9-10 L30-17, p. 16 L13-22, p. 23 L15-16, p. 24 L1-7, and other instances as well) any myostatin receptor can be inhibited with RNAi molecules and the “single sentence” that mentions ALK4 and ALK5 is in the section called (p. 33) B. Gene targets for therapy, subsection (p. 34) Myostatin receptors. What’s more, WO002 discusses (p. 13 L25-34) the oligont sequence (that comprises the RNAi molecule) can be derived from any of the genes listed in Tables I and 2, or any other gene the modulation of whose expression is likely to produce a desirable therapeutic result in a muscle-wasting condition [emphasis added]. Based on the teachings of WO988, an artisan would know that targeting ALK4 and ALK5 are genes the modulation of whose expression is likely to produce a desirable therapeutic result in a muscle-wasting condition. The rejection is based on the combination of references, and it is the combination of references that provides a reasonable expectation of success.
The 103 rejection is maintained for those reasons.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUTHIE S ARIETI whose telephone number is (571)272-1293. The examiner can normally be reached M-Th 8:30AM-4PM, alternate Fridays 8:30AM-4PM (ET).
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RUTHIE S ARIETI
Examiner
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636
