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, 3, 6-8, 40, 42, 45-49, and 90-97 are pending.
Election/Restrictions
Applicant’s election of Group I, drawn to methods of increasing muscle weight/reducing body fat content/improving glucose metabolism in a subject (Claims 1, 3, 6-8, and 90-93), in the reply filed on 22 May 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 40, 42, 45-49, and 94-97 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 22 May 2026.
Claims 1, 3, 6-8, and 90-93 are examined.
Information Disclosure Statement
The IDS has been considered.
The Spec. cites references.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because the text and figures are blurry/dim/low quality. (Figs. 4C, 10, and 11 are fine.)
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the following term(s):
R&D systems® (p. 61 L11),
Scanco® (p. 61 L27),
Zeiss® (p. 61 L18),
Sepharose® (p. 61 L25),
Nikon® (p. 74 L29),
which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Applicant is responsible for identifying and remediating any other instances of any trade names or marks.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
The claims recite myofibers. The Spec. indicates (p.28 L10-13) myofibers are simply muscle cells.
The claims recite …relative to a control or baseline. “Baseline” is interpreted as meaning the state of the muscle before it is treated with any agent.
Claim Objections
Claims 1, 3, 6-8 are objected to because of the following informalities:
Claims 1 and claims depending therefrom recite ALK4 and ALK5. Those should be spelled out on first use in Claim 1: …Activin A Receptor Type 1B (ALK4) and Transforming Growth Factor β Receptor Type 1 (ALK5)…
Claims 3 and 6-8 recite …an effective amount to… but will be better if they recite …an amount effective to….
Claim 8 further recites …to increase gastrocnemius/plantaris muscle weight. The claim will be better if it recites …to increase gastrocnemius and/or plantaris muscle weight. In the interest of compact prosecution the claim is interpreted as if it recites …to increase gastrocnemius and/or plantaris muscle weight.
Appropriate correction is required.
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, 3, 6-8, and 90-93 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.
Claim 1 recites a method of increasing muscle weight, reducing body fat content, and/or improving glucose metabolism in a subject, the method comprising administering to the subject an agent or combination of agents that inhibits ALK4 and ALK5 signaling in myofibers of the subject. Claims 90-93 recite the method wherein the agent or combination of agents comprises first and second ASOs (Claim 90), shRNAs (Claim 91), siRNAs (Claim 92), and miRNAs (Claim 93).
The broad claims encompass the large genus of agents that inhibit ALK4 and ALK5 (i.e., Claims 1 and claim depending therefrom) and the large subgenera of ASO/shRNA/siRNA/miRNA agents that inhibit ALK4 and ALK5 (i.e., Claims 90-93). Any kind of agent(s)/ASO(s)/shRNA(s)/siRNA(s)/miRNA(s) that inhibits ALK4 and ALK5 would be encompassed by the claims as instantly presented. Note that the claims encompass not only agents that directly inhibit ALK4/ALK5, but also any agent(s) that modulates players that operate upstream of ALK4/ALK5 and whose modulation would result in inhibition of ALK4/ALK5.
There is a written description problem because Applicant has not disclosed any physical structure that is responsible for the recited inhibiting ALK4 and ALK5. Although Claims 90-93 recite that the ASO/shRNA/siRNA/miRNA agents target RNA encoding ALK4/ALK5, such agents 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 in any way that demonstrates Applicant was in possession of the full scope of the claimed method.
Regarding what structure is encompassed by the agents that inhibit(s) ALK4 signaling and ALK5 signaling, the Spec. does not provide information describing its 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 agents that inhibit ALK4 and ALK5 and the large subgenera of ASO/shRNA/siRNA/miRNA agents that inhibit ALK4 and ALK5, as well as any agent(s) that modulates players that operate upstream of ALK4/ALK5 and whose modulation results in inhibition of ALK4/ALK5. Floxed alleles are not agents that can be administered to a subject. Although the claims claim the functional characteristics (i.e., inhibiting ALK4/ALK5 signaling and inhibiting ALK4/ALK5 signaling by using ASO/shRNA/siRNA/miRNA agents to target RNA encoding ALK4/ALK5), 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 inhibiting ALK4/ALK5 signaling or inhibiting ALK4/ALK5 signaling by using ASO/shRNA/siRNA/miRNA agents to target RNA encoding ALK4/ALK5. 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 inhibiting ALK4/ALK5 signaling or inhibiting ALK4/ALK5 signaling by using ASO/shRNA/siRNA/miRNA agents to target RNA encoding ALK4/ALK5 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 agent, including any small molecule, peptide, nuclease-based gene editing molecules, ASO/shRNA/siRNA/miRNA that inhibit, in any manner and including by inhibiting any upstream players, ALK4 and ALK5. 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 agent, including any small molecule, peptide, nuclease-based gene editing molecules, ASO/shRNA/siRNA/miRNA that targets ALK4/ALK5 or any player in the pathway whose modulation would result in inhibition of ALK4/ALK5. Nothing in the Spec. discloses what physical structure of ALK4/ALK5 inhibiting agents is responsible for increasing weight of any general muscle, or the specific muscles tricep/quadricep/gastrocnemius/plantaris by at least 3-5% relative to a control agent or to baseline.
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 90-93 are rejected for failing to demonstrate possession of the claimed invention. Claims 3, 6-8, and 90-93 are rejected because they depend from Claim 1 and do not remedy the issues.
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 3, and 6-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by 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). 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 ALK5 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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Therefore WO988 anticipates Claim 1.
Regarding Claims 3 and 6-8, 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 those recited in the claims: tricep, quadricep, and gastrocnemius/plantaris. Therefore WO988 anticipates Claims 3 and 6-8.
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, 3, 6-8, and 90-93 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) as applied to Claims 1, 3, and 6-8 in the 102 rejection above, and further 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”), and NCBI (Homo sapiens activin A receptor type 1B [ACVR1B], transcript variant 1, mRNA. version archived 02 May 2019. Accessed 08 June 2026, “NCBI”).
All citations to WO document p. #s refer to PDF p. #.
The disclosures of WO988 as evidenced by Han as applicable to Claim(s) 1, 3, and 6-8 have been described above.
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.
WO988 teaches (pp. 4-5 L13-15) small molecule inhibitors.
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. 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.
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.
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). 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 and have a short research/development timeline) 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 decrease body fat by inhibiting both ALK4 and ALK5. WO269 clearly demonstrates nucleic acid–based therapies for targeting (and inhibiting) mRNA encoding ALK5 were envisioned.
Regarding (2): WO988 teaches inhibiting only two proteins: ALK4 and ALK5. 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 a 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.
Therefore, Claims 90-93 (and 1, 3, and 6-8) would have been obvious in view of WO988, WO269, Hu, and NCBI.
Claim(s) 1, 3, and 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over WO988 as evidenced by Han as applied to Claims 1, 3, and 6-8 in the 102 rejection above, and further in view of McPherron (et al. 2013. Increasing muscle mass to improve metabolism. Adipocyte 2[2]:92-98, “McPherron”).
All citations to WO document p. #s refer to PDF p. #.
The disclosures of WO988 as evidenced by Han as applicable to Claim(s) 1, 3, and 6-8 have been described above.
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.
WO988 as evidenced by Han does not explicitly discuss using their method to improve glucose metabolism (an alternate limitation of Claim 1).
However, McPherron, drawn to increasing muscle mass to improve metabolism, teaches (§Exercise and Exercise Mimetics for Fighting Insulin Resistance ¶2-6) more muscle mass corresponds with less insulin resistance:
(¶2) signaling pathways that promote muscle hypertrophy are potential targets for resistance exercise mimetics that may have the added benefit of preventing or treating muscle insulin resistance; (¶4) blocking MSTN signaling in muscle also affects whole body metabolism… Mice with Mstn gene deletion, transgenic mice with overexpression of a dominant negative ACVR2B… are muscular and resistant to the metabolic consequences of high-fat feeding including obesity, insulin resistance and atherosclerosis… Soluble MSTN inhibitors prevent diet-induced obesity (DIO) and insulin resistance when given at the onset of high-fat diet feeding…
McPherron further teaches blocking myostatin signaling improves glucose tolerance: (Muscle Hypertrophy in Lipodystrophic Mice)
MSTN inhibitors are currently in development for treating muscle wasting conditions. They may also be beneficial for improving some aspects of metabolic dysfunction even though they have been unsuccessful at inducing weight loss in obese rodents. Notably, glucose tolerance and fasting glucose were improved in ob/ob mice treated with anti-MSTN antibodies.
That indicates it was well-known in the art that blocking myostatin signaling improves glucose metabolism. As discussed previously, WO988 is directed to using ALK and ALK5 inhibitors to block myostatin signaling.
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 inhibiting myostatin activity by using ALK4 and ALK5 inhibitors with the teachings of McPherron for the benefit of using ALK4/ALK5 inhibitors to increase muscle mass and improve glucose metabolism in animals. One would have done so with a reasonable expectation of success because McPherron teaches blocking myostatin signaling improves glucose metabolism and WO988 teaches using ALK4/ALK5 inhibitors to block myostatin signaling. Improving glucose metabolism would have been an outcome of using WO988’s method.
Therefore all limitations of Claim 1, including the alternate limitation, would have been obvious in view of WO988 (as evidenced by Han) and McPherron.
Claim(s) 1, 3, 6-8, and 90-93 are rejected under 35 U.S.C. 103 as being unpatentable over WO988 as evidenced by Han as applied to Claims 1, 3, and 6-8 in the 102 rejection above, and further in view of International Publication Number International Publication Number WO 2008/005002 (published 10 January 2008, “WO002”).
All citations to WO document p. #s refer to PDF p. #.
The disclosures of WO988 as evidenced by Han as applicable to Claim(s) 1, 3, and 6-8 have been described above.
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.
WO988 as evidenced by Han does not explicitly discuss using their method to improve glucose metabolism (an alternate limitation of Claim 1). WO988 as evidenced by Han does not explicitly discuss the effect of their method on the muscles named triceps, quadriceps, and/or gastrocnemius (limitations of Claims 6-8) .
However, teachings of WO002, drawn to oligonucleotides (oligont) that target the myostatin signaling pathway, would have made it obvious to use the method of WO988 to increase tricep, quadriceps, and/or gastrocnemius weight by at least 3-5% or more.
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: DMD, sarcopenia, and diabetes mellitus. WO002 discloses (p. 2 L15-18) their invention promotes muscle growth.
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.
Regarding the limitation about improving glucose metabolism of Claim 1, WO002 teaches (p. 36 L7-31) myostatin KO mice have less fat accumulation, lower blood glucose, and lower insulin vs. their counterparts with wildtype myostatin, indicating that inhibition of myostatin may be used to treat for type 2 diabetes.
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 treat type 2 diabetes and thereby improve glucose metabolism.
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) to treat type 2 diabetes. 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 type 2 diabetes 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 type 2 diabetes. It would have been a simple matter to use WO988’s method of inhibiting ALK4 and ALK5 to also treat diabetes, and doing so would have improved glucose metabolism in a subject. Therefore all limitations of Claim 1 would have been obvious in view of the teachings of WO988 and WO002.
Regarding the muscles named in Claims 6-8: WO002 discusses (§Example 2, pp. 53-55 L11-6; §Example 6, pp. 59-61 L22-10; Fig. 5) using oligont targeted to myostatin to increase muscle mass in tricep, quadricep, and/or gastrocnemius muscles by as much as 8.8-26% vs. control. That indicates it was routine in the art to quantify a treatment’s effect on muscle weight by measuring the weight of the tricep, quadricep, and/or gastrocnemius muscles before and after treatment or after treatment vs. baseline.
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 inhibiting myostatin signaling to increase the weight of tricep, quadricep, and gastrocnemius muscles by at least 3-5% vs. baseline/control for the benefit of using the method to increase weight of major muscles in the body. One would have been motivated to do so with a reasonable expectation of success because WO002 teaches their methods encompass inhibiting myostatin or a myostatin receptor, and teaches they demonstrated efficacy of their methods by increasing the weight of tricep, quadricep, and gastrocnemius muscles. Since WO988 teaches their method of inhibiting ALK4 and ALK5 increases muscle weight by 5-15%, an artisan would have reasonably expected the method to increase the weight of any skeletal muscle, including the specific muscles tricep, quadricep, and gastrocnemius—whose weights it was routine and conventional to measure—by at least 5-15%. Therefore all limitations of Claims 6-8 would have been obvious in view of the teachings of WO988 and WO002.
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, 6-8, and 90-93 are rejected on the ground of nonstatutory double patenting as being unpatentable over the following claims of the following U.S. Patents in view of 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); 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”), NCBI (Homo sapiens activin A receptor type 1B [ACVR1B], transcript variant 1, mRNA. version archived 02 May 2019. Accessed 08 June 2026, “NCBI”), International Publication Number International Publication Number WO 2008/005002 (published 10 January 2008, “WO002”), and Wikipedia (“microRNA”. Page archived on 07 November 2020, “Wikipedia”).
Patent No.
App. No.
Claims
Notes
US6656475
09/626896
All
Methods of inhibiting myostatin and ameliorating muscle wasting
US6500664
09/629938
Claim 11
Oligont fragments that would inhibit myostatin (a.k.a. GDF8)
US6858208
10/278803
All
Methods for inhibiting GDF8 (using antibodies) and increasing muscle mass
US7572599
10/665374
All
Methods of modulating myostatin activation, including (Claim 5) inhibiting myostatin activation
US7534432
11/700267
All
Methods of treating musculodegenerative condition by suppressing GDF8 activity
Although the claims at issue are not identical, they are directed to overlapping subject matter because the instant claims are directed to methods of inhibiting ALK4 and ALK5 and using nucleic acid–based inhibitors to inhibit ALK4 and ALK5 and thereby increase muscle mass in an animal.
The patented claim sets are directed to methods of inhibiting myostatin signaling or activation (including to increase muscle mass or treat muscle wasting in an animal and to decrease fat content), methods of treating a disease/condition by suppressing GDF8 activity, and/or to compounds for inhibiting myostatin or compounds that bind genomic sequence encoding myostatin. Note that GDF8 is simply another way to abbreviate myostatin.
Both claim sets are directed to methods or compounds for inhibiting myostatin signaling, including to increase muscle mass in an animal.
The patented claim sets don’t teach using ALK4 and ALK5 inhibitors or nucleic acid–based ALK4 and ALK5 inhibitors to increase muscle mass in an animal (including by 3-5% in specific muscles). However, those limitations would have been obvious in view of the prior art:
WO988 is drawn to using ALK5 inhibitors to inhibit myostatin signaling and thereby increase lean muscle mass in animals and discloses (p. 4 L12-18, p. 6 L8-11, p. 7 L8-11, p. 15 L6-19, p. 16 L9-17; p. 20 L16-17, pp. 15-16 L20-9) an ALK5/ALK4 dual inhibitor that increases muscle mass (including by at least 3-5%) and decreases fat tissue in animals (including in humans), and that inhibiting both ALK4 and ALK5 produces desirable effects by inhibiting signaling through the ALK4 and ALK5 receptors.
Han provides evidence that (Fig. 2) ALK4/ALK5 signaling occurs in muscle, indicating that inhibition of ALK4/ALK5 occurs in myofibers/muscle cells. Based on Han, an artisan would have understood that inhibiting myostatin would inhibit ALK4 and ALK5 signaling.
WO269 discloses (pp. 7-13 L30-10, p. 41 L6-10, p. 9 L1-13) ALK5 inhibitors, including 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 that [§Abstract] induce skeletal muscle hypertrophy).
Hu, drawn to a review about nucleic acid therapies, teaches (§Abstract, §Introduction ¶1-6) RNA interference therapies are specific to any gene of interest and can be developed quickly, and are longer-lasting than small molecules or antibodies.
NCBI demonstrates that the sequence of ALK4 was known.
The teachings of WO002 (§Abstract, p. 2 L1-18, p. 4 L17-20, p. 34 L16-20, §Example 2, pp. 53-55 L11-6; §Example 6, pp. 59-61 L22-10; Fig. 5) would have made it obvious to inhibit any part of the myostatin signaling pathway to (1) increase muscle mass in an animal, (2) increase tricep, quadriceps, and/or gastrocnemius weight by at least 3-5% or more; and (3) improve glucose metabolism.
Regarding the claim of US6500664, Claim 11 recites an oligont fragment that binds to GDF8 genomic DNA. Wikipedia provides evidence that miRNA can bind to genomic DNA. Wikipedia discloses (§Cellular functions ¶3) miRNAs occasionally also cause histone modification and DNA methylation of promoter sites, which affects the expression of target genes.
Therefore it would have been obvious before the effective filing date of the claimed invention to modify the compounds and methods of the patented claims with the teachings of WO988, Han, WO269, Hu, NCBI, and WO002 for the benefits of inhibiting ALK4 and ALK5 expression and increasing muscle mass in animals. One would have been motivated to do so with a reasonable expectation of success because the artisan would have known (based on the teachings of Han and WO002) that inhibiting myostatin would inhibit ALK4 and ALK5 signaling. They would have been motivated to directly inhibit ALK4 and ALK5 signaling to inhibit myostatin signaling and thereby increase muscle mass in an animal because they would have known (based on the teachings of WO988, Han, and WO002) that inhibiting ALK4 and ALK5 signaling would inhibit myostatin signaling since myostatin signals through ALK4 and ALK5. An artisan would have been motivated to use the nucleic acid–based inhibition strategies of Hu because Hu teaches nucleic acid–based therapies are specific, long-lasting, and can be developed quickly, and because WO002 teaches inhibiting any myostatin receptor treats muscle wasting. Evidence from Wikipedia indicates that the miRNAs that would have been obvious in view of the cited art would bind myostatin genomic DNA and regulate its expression to inhibit it.
Therefore the claimed invention would have been obvious in view of the patented claims, WO988, Han, WO269, Hu, NCBI, and WO002 and evidence from Wikipedia.
Claims 1, 3, 6-8, and 90-93 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9, 25, 34, and 42-43 of US Pat. No. 6,497,729 (“US729”) in view of WO988 as evidenced by Han; WO269, Hu, NCBI, and WO002.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the instant claims are directed to methods of inhibiting ALK4 and ALK5 and using nucleic acid–based inhibitors to inhibit ALK4 and ALK5 and thereby increase muscle mass in an animal.
The patented claims are directed to an implant that provides a tissue response modifier to its site of implantation, wherein the tissue response modifier can be an anti-TGFBR antibody and wherein the implant can be placed at the muscles and can be a repair device. Note that TGFRB is simply another way to abbreviate ALK5.
Both claim sets are directed to methods or compounds for inhibiting ALK5 signaling, including to improve—“repair” or increase—muscles in an animal.
The patented claim sets don’t teach using an ALK4 inhibitor or nucleic acid–based ALK4 and ALK5 inhibitors to increase muscle mass in an animal (including by 3-5% in specific muscles). However, those limitations would have been obvious in view of the prior art:
WO988 is drawn to using ALK5 inhibitors to inhibit myostatin signaling and thereby increase lean muscle mass in animals and discloses (p. 4 L12-18, p. 6 L8-11, p. 7 L8-11, p. 15 L6-19, p. 16 L9-17; p. 20 L16-17, pp. 15-16 L20-9) an ALK5/ALK4 dual inhibitor that increases muscle mass (including by at least 3-5%) and decreases fat tissue in animals (including in humans), and that inhibiting both ALK4 and ALK5 produces desirable effects by inhibiting signaling through the ALK4 and ALK5 receptors.
Han provides evidence that (Fig. 2) ALK4/ALK5 signaling occurs in muscle, indicating that inhibition of ALK4/ALK5 occurs in myofibers/muscle cells.
WO269 discloses (pp. 7-13 L30-10, p. 41 L6-10, p. 9 L1-13) ALK5 inhibitors, including 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 that [§Abstract] induce skeletal muscle hypertrophy).
Hu, drawn to a review about nucleic acid therapies, teaches (§Abstract, §Introduction ¶1-6) RNA interference therapies are specific to any gene of interest and can be developed quickly, and are longer-lasting than small molecules or antibodies.
NCBI demonstrates that the sequence of ALK4 was known.
The teachings of WO002 (§Abstract, p. 2 L1-18, p. 4 L17-20, p. 34 L16-20, §Example 2, pp. 53-55 L11-6; §Example 6, pp. 59-61 L22-10; Fig. 5) would have made it obvious to inhibit any part of the myostatin signaling pathway—including ALK4 and ALK5—to (1) increase muscle mass in an animal, (2) increase tricep, quadriceps, and/or gastrocnemius weight by at least 3-5% or more; and (3) improve glucose metabolism.
Therefore it would have been obvious before the effective filing date of the claimed invention to modify the implant that releases an anti-TGFBR antibody of the patented US729 claims with the teachings of WO988, Han, WO269, Hu, NCBI, and WO002 for the benefits of inhibiting ALK4 and ALK5 expression and increasing muscle mass in animals. One would have been motivated to do so with a reasonable expectation of success because the artisan would have known (based on the teachings of Han and WO988) that inhibiting ALK4 and ALK5 signaling would increase muscle mass. They would have been motivated to use the nucleic acid–based inhibition strategies of Hu because Hu teaches nucleic acid–based therapies are specific, long-lasting, and can be developed quickly, and because WO002 teaches inhibiting any myostatin receptor treats muscle wasting. It would have been obvious to modify the US729 claims with the teachings of WO988, Han, WO269, Hu, NCBI, and WO002 for the benefit of inhibiting both ALK5 and ALK4 to increase muscle mass as taught by WO988. It would have been a simple matter to place the ALK4- and ALK5-targeting nucleic acid–base inhibitors of WO988, Han, WO269, Hu, NCBI, and WO002 within the muscle-implantable device of the US729 claims and one would have been motivated to do so with a reasonable expectation of success for the benefits discussed by WO988 and because the US729 claims allow any of a long list of modifiers to be placed within their device.
Therefore the claimed invention would have been obvious in view of the patented claims, WO988, Han, WO269, Hu, NCBI, and WO002.
Claims 1, 3, 6-8, and 90-93 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of US Pat. No. 10,842,826 (“US826”) in view of WO988 as evidenced by Han; WO269, Hu, NCBI, and WO002.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the instant claims are directed to methods of inhibiting ALK4 and ALK5 and using nucleic acid–based inhibitors to inhibit ALK4 and ALK5 and thereby increase muscle mass in an animal.
The patented claims are directed to methods for tissue (including muscle) regeneration and repair by administering cells in a medium that comprises an ALK5 inhibitor.
Both claim sets are directed to methods that comprise inhibiting ALK5 signaling, including to regenerate muscle in an animal.
The patented claim sets don’t teach using an ALK4 inhibitor or nucleic acid–based ALK4 and ALK5 inhibitors to increase muscle mass in an animal (including by 3-5% in specific muscles). However, those limitations would have been obvious in view of the prior art:
WO988 is drawn to using ALK5 inhibitors to inhibit myostatin signaling and thereby increase lean muscle mass in animals and discloses (p. 4 L12-18, p. 6 L8-11, p. 7 L8-11, p. 15 L6-19, p. 16 L9-17; p. 20 L16-17, pp. 15-16 L20-9) an ALK5/ALK4 dual inhibitor that increases muscle mass (including by at least 3-5%) and decreases fat tissue in animals (including in humans), and that inhibiting both ALK4 and ALK5 produces desirable effects by inhibiting signaling through the ALK4 and ALK5 receptors.
Han provides evidence that (Fig. 2) ALK4/ALK5 signaling occurs in muscle, indicating that inhibition of ALK4/ALK5 occurs in myofibers/muscle cells.
WO269 discloses (pp. 7-13 L30-10, p. 41 L6-10, p. 9 L1-13) ALK5 inhibitors, including 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 that [§Abstract] induce skeletal muscle hypertrophy).
Hu, drawn to a review about nucleic acid therapies, teaches (§Abstract, §Introduction ¶1-6) RNA interference therapies are specific to any gene of interest and can be developed quickly, and are longer-lasting than small molecules or antibodies.
NCBI demonstrates that the sequence of ALK4 was known.
The teachings of WO002 (§Abstract, p. 2 L1-18, p. 4 L17-20, p. 34 L16-20, §Example 2, pp. 53-55 L11-6; §Example 6, pp. 59-61 L22-10; Fig. 5) would have made it obvious to inhibit any part of the myostatin signaling pathway—including ALK4 and ALK5—to (1) increase muscle mass in an animal, (2) increase tricep, quadriceps, and/or gastrocnemius weight by at least 3-5% or more; and (3) improve glucose metabolism.
Therefore it would have been obvious before the effective filing date of the claimed invention to modify the method of the patented US826 claims with the teachings of WO988, Han, WO269, Hu, NCBI, and WO002 for the benefits of inhibiting ALK4 and ALK5 expression and increasing muscle mass in animals. One would have been motivated to do so with a reasonable expectation of success because the artisan would have known (based on the teachings of Han and WO988) that inhibiting ALK4 and ALK5 signaling would increase muscle mass. The patented US826 claims allow using any ALK5 inhibitor in the method to regenerate muscle, and an artisan would have been motivated to use the nucleic acid–based inhibition strategies of Hu because Hu teaches nucleic acid–based therapies are specific, long-lasting, and can be developed quickly, and because WO002 teaches inhibiting any myostatin receptor treats muscle wasting. It would have been obvious to modify the US826 claims with the teachings of WO988, Han, WO269, Hu, NCBI, and WO002 for the benefit of inhibiting both ALK5 and ALK4 to increase muscle mass as taught by WO988. It would have been a simple matter to use the ALK4- and ALK5-targeting nucleic acid–base inhibitors of WO988, Han, WO269, Hu, NCBI, and WO002 in the methods of the US826 claims and one would have been motivated to do so with a reasonable expectation of success for the benefits discussed by WO988 and because the US826 claims allow any ALk5 inhibitor.
Therefore the claimed invention would have been obvious in view of the patented claims, WO988, Han, WO269, Hu, NCBI, and WO002.
Conclusion
No claim is allowed.
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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
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