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 1-4, 6, 9, 11, 15-16, 20, 23, 26-32, 34-36, 38-39, and 42 are pending.
Status of the Application
Applicant’s response and amendment filed 03 August 2026 are acknowledged and entered.
Applicant has amended Claims 1-4, 6, and 42. Applicant has cancelled Claim 8.
Applicant has amended the Spec. to overcome Objections to the Spec and Drawings; the objections are withdrawn.
Applicant has amended Claims 1-4 and 6 to overcome the 112(a) Written Description rejection; the 112(a) rejection is withdrawn. See also §Response to Arguments.
Applicant has amended Claim 42 to overcome the 112(a) Scope of Enablement; the 112(a) rejection is withdrawn.
Applicant has amended Claim 42 to overcome the 112(a) Scope of Enablement; the 112(a) rejection is withdrawn.
The 103 and NSDP rejections are maintained.
Claims 1-4, 6, 9, 11, 15-16, 20, 23, 26-32, 34-36, 38-39, and 42 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Rejections not reiterated here are withdrawn.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 …at least 80% identity to a nucleotide sequence selected from the group consisting of SEQ ID NO 2, SEQ ID NO 3, and SEQ ID NO 4; and wherein the inhibitory nucleic acid targets Salvador. The recitation wherein the inhibitory nucleic acid targets Salvador is interpreted as a function resulting from the structure of a nucleic acid having at least 80% identity to SEQ ID NOs 2-4.
The claims recite a nucleic acid construct. That is defined in the Spec. ¶56 as a synthesized nucleic acid molecule comprising one or more functional nucleotide sequences. The claims recite operably linked. That is defined in the Spec. ¶57 as refer[ring] to the association of nucleic acid sequences on a polynucleotide so that the function of one of the sequences is affected by another.
Claim 26 recites …wherein the nucleotide sequences are expressed in the skeletal muscle cells. Claim 26 depends from Claim 1 which recites …the method comprising delivering to skeletal muscle cells… therefore wherein the nucleotide sequences are expressed in the skeletal muscle cells is interpreted as an outcome of carrying out the method step of delivering.
Claim 28 recites a nucleic acid having the nt sequence set forth in SEQ ID NO…. “Having” is interpreted as open language, the same as “comprising”.
REJECTIONS REITERATED FROM OFFICE ACTION DATED 18 MARCH 2026
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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) 1-4, 6, 8-9, 11, 15-16, 20, 23, 36-32, 34, 38-39, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over: Plouffe (et al. 2015. Disease implications of the Hippo/YAP pathway. Trends Molec. Med. 21[4]:212-222, “Plouffe”), He (et al. 2017. The role of Hippo/yes-associated protein signalling in vascular remodelling associated with cardiovascular disease. Brit. J. Pharmacol. 175:1354-1361, “He”), Choi (et al. 2015. Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2. Nat. Comm. 6:6943, “Choi”), Lee (et al. 2010. The Hippo–Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. PNAS 107[8]:8249-8253, “Lee”), Zhou (2014. An emerging role for Hippo-YAP signaling in cardiovascular development. J. Biomed. Res. 28[4]:251-254, “Zhou”), Watt (et al. April 2019. Author manuscript of The Hippo Signaling Pathway in the Regulation of Skeletal Muscle Mass and Function. Exerc. Sport Sci. Rev. 46[2]:92-96, “Watt”, published version of record on IDS), Watt (et al. 2015. The Hippo pathway effector YAP is a critical regulator of skeletal muscle fibre size. Nat. Comm. 6:6048, “Watt 2015”), International Publication Number WO 2015/089074 (published 18 June 2015, “WO074” of record on IDS) as evidenced by Wikipedia (“Post transcriptional regulation”. page archived 25 October 2020. Available at Wikipedia.org. Accessed on 11 March 2026, “Wikipedia”), International Publication Number WO 2019/051117 (published 14 March 2019, “WO117”, of record on IDS), and Wikipedia ("WHP Posttransciptional Response Element". page archived 09 March 2018. Available at Wikipedia.org. Accessed on 11 March 2026, “Wikipedia”). All references are of record. This rejection is maintained.
The prior art teaches Salvador (SAV1) and YAP are in the same signaling pathway and teaches a connection between the presence of SAV1 and amount of YAP was known. The prior art also teaches connections between the Hippo pathway and each of the claimed outcomes.
Plouffe teaches (§Abstract) the Hippo signaling pathway is important for controlling organ size and tissue homeostasis. Plouffe teaches (Fig. 1) SAV1 is upstream of YAP in the Hippo pathway:
SAV1 [together in complex with another protein partner] phosphorylate and activate [LATS1/2] and [MOB1]. When activated, LATS1/2 phosphorylates [YAP/TAZ], the primary effectors of the Hippo pathway. When phosphorylated, YAP/TAZ are sequestered in the cytoplasm or degraded. When YAP/TAZ are dephosphorylated, they translocate to the nucleus where they interact with [TEAD1–4] to induce transcription and promote cell proliferation and inhibit apoptosis.
Plouffe teaches (§The Hippo pathway in intestinal regeneration) YAP plays an important role in regeneration following injury and (§The Hippo pathway in cardiomyocyte regeneration):
SAV1-deficient cardiomyocytes can re-enter the cell cycle and undergo cell division and SAV1 heart-specific knockout mice show improved recovery following ischemia, with ejection fraction and fractional shortening values comparable to those of control, non-ischemic mice [58]. These reports suggest that Hippo-deficient hearts exhibit increased regenerative potential. YAP transgenic mice also show increased regeneration and decreased fibrosis following heart injury.
Those teachings indicate that the Hippo pathway was known to be involved in cell regenerative potential.
He, drawn to the role of Hippo pathway component YAP in vascular remodelling, teaches (§Introduction ¶2) Hippo/Yap signaling was found to contribute to vascular remodelling and related CVDs, including pulmonary hypertension, atherosclerosis, aortic aneurysms, restenosis and angiogenesis. He teaches (§Components of the Hippo/YAP pathway, Fig. 1) YAP is a transcriptional enhancer that is downstream of SAV1. He teaches (§Hippo/YAP pathway and angiogenesis) angiogenesis is an important process to form new blood vessels under both physiological and pathophysiological conditions and angiogenesis is involved in ischaemia-induced vascular remodelling, which restores perfusion in some ischaemic conditions, such as acute myocardial infarction and hind-limb ischaemia. He teaches (same §) YAP deficiency leads to defective tubular network formation of ECs and suppresses angiogenesis. He teaches (same §) these findings imply that YAP might be a potent therapeutic target to regulate angiogenesis for ischaemic diseases.
Both Plouffe and He indicate that SAV1 is upstream of and negatively regulates YAP’s functions (which include angiogenesis and cell growth and proliferation) by resulting in YAP phosphorylation which keeps it out of the nucleus. Both Plouffe and He teach that nuclear YAP is necessary for downstream functions such as angiogenesis (which restores perfusion in limb-ischemia) to occur.
Choi, drawn to YAP’s regulation of ANG2 expression and, therefore, angiogenesis, teaches (§Abstract) over-expression of YAP-active form in endothelial cells (EC) enhances angiogenic sprouting. Choi teaches (Fig. 2) YAP deficient EC display impair angiogenesis.
Together, He’s and Choi’s teachings indicate increasing the amount of YAP in a cell’s nucleus induces angiogenesis and suggest YAP as a therapeutic target for regulating angiogenesis to treat ischemic diseases including hind limb ischemia. Conversely, He and Choi teach that decreasing YAP decreases angiogenesis.
Lee, drawn to the Hippo pathway in liver cell proliferation and size, teaches (§Abstract) ablation of WW45 increased the abundance of YAP and induced its localization to the nucleus in oval cells, likely accounting for their increased proliferative capacity. Lee teaches (same §) WW45 is simply another name for SAV1. Zhou, drawn to Hippo pathway role in cardiovascular development, teaches (§ROLE OF YAP IN MOUSE CARDIOVASCULAR DEVELOPMENT) the YAP gain-of-function phenotype in mouse heart largely phenocopies the cardiac-specific knockout of SAV1.
In addition, the teachings of Watt indicate that (§The Hippo signaling pathway, Fig. 1) the Hippo pathway works the same way in skeletal muscle as in other tissues described in Plouffe, He, Choi, Lee, and Zhou: SAV1 acts, upstream in the pathway and with a partner, to phosphorylate and downregulate YAP, thereby inhibiting YAP. Watt teaches (§Introduction ¶1) key elements of the Hippo signaling pathway, an essential mediator of tissue growth in a number of epithelial cell types, function during adult skeletal muscle fiber growth. Watt teaches (same §) their findings indicate the Hippo pathway is a critical element in both muscle fibers and muscle satellite cells. Watt teaches (§Yap and Taz expression in skeletal muscle) YAP is controlled by negative feedback mechanisms and amount of YAP increases during chronic mechanical overload-induced hypertrophy in mouse skeletal muscle (suggesting an anabolic role), and that YAP supports skeletal muscle regeneration. Watt teaches (same §) a reduction in YAP plays a role in age-dependent loss of skeletal muscle mass (i.e., sarcopenia). Watt teaches (§The functional role of Yap and Taz during satellite cell activation) transient activation of YAP enhances satellite cell proliferative dynamics and permits myoblast differentiation to support skeletal muscle growth and adaptation. Watt teaches (§Yap and Taz promote muscle growth via Tead in Post-natal muscle fibers) YAP stimulates muscle fiber hypertrophy.
Together, Watt’s teachings indicate that YAP functions to increase proliferation of satellite cells and increase muscle hypertrophy, and that YAP supports skeletal muscle regeneration. Watt’s teachings also indicate that (Fig. 1) Hippo signaling in skeletal muscle works the same as in other cells and tissues: SAV1 negatively regulates YAP.
Watt 2015 teaches (§Abstract) YAP positively regulates basal skeletal muscle mass and protein synthesis. Watt 2015 teaches (§YAP is required to maintain basal skeletal myofibre size) injecting to mouse skeletal muscle AAV encoding a YAP-targeting shRNA and (§YAP promotes hypertrophy via TEAD transcription factors) injecting to mouse skeletal muscle AAV encoding a YAP. Watt 2015 teaches (same § and Figs. 1a and 3a) increasing YAP expression resulted in an increase in muscle mass and mean myofiber cross-sectional area (CSA). Watt 2015 teaches (same §) these results support the hypothesis that YAP positively regulates muscle mass, and that increasing YAP levels is sufficient to promote muscle hypertrophy in vivo [emphasis added]. Watt 2015 teaches (§Abstract) YAP abundance and activity in muscles is increased following injury or degeneration of motor nerves, as a process to mitigate neurogenic muscle atrophy. Watt 2015 suggests (same §) further investigation to identify interventions that promote YAP activity in skeletal muscle might aid the development of therapeutics to combat muscle wasting and neuromuscular disorders.
Watt 2015’s teachings indicate it was routine and conventional in the art of increasing skeletal muscle mass to administer via intramuscular injection to skeletal muscle an AAV vector encoding shRNA or encoding a gene to up- or down-regulate a target within the Hippo pathway. Watt 2015’s teachings indicate that increasing YAP levels was known to promote muscle hypertrophy in vivo.
Therefore, in view of the teachings of Plouffe, He, and Choi, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that upregulating the amount of cellular YAP would increase angiogenesis and treat limb ischemia (i.e., some limitations of Claims 1, 4, 39, and 42). It would also have been obvious, in view of the teachings of Lee and Zhou, that downregulating the amount of SAV1 would be one way to effectively upregulate the amount of YAP. It would also have been obvious, in view of the teachings of Watt and Watt 2015, that the Hippo pathway works the same in skeletal muscle as other tissues and that increasing YAP would increase skeletal muscle mass and proliferation of satellite cells and increase skeletal muscle regeneration; all of those functions are simply another way of saying “regenerating myofibers” (some limitations of Claims 2 and 3). It would have been obvious, in view of the teachings of Watt, to increase YAP to treat sarcopenia (i.e., a limitation of Claim 42). The teachings of Watt 2015 indicate that upregulating YAP increases muscle mass and muscle fiber cross-sectional area, so it would have been obvious to upregulate YAP, including by downregulating SAV1, to increase skeletal muscle mass.
Plouffe, He, Choi, Lee, Zhou, Watt, and Watt 2015 do not teach administering an inhibitory nucleic acid having or encoded by a sequence having identity to claimed SEQ ID NOs 2, 3, and/or 4, or the other claim limitations.
However, WO074, drawn to Hippo and dystrophin complex signaling in cardiomyocyte renewal, teaches (¶8) shRNA that targets any member of the Hippo pathway, including SAV1. Although WO074 is drawn to treating cardiac conditions, it teaches (¶51) treating individuals suffering from degeneration of skeletal muscle fibers.
Regarding the SEQ ID NOs recited in the claims and Claims 8-9 and 11: WO074 teaches (¶9) using nucleic acid compositions that target SAV1 in a mammal, the nucleic acid compositions are shRNA molecules, and the compositions can comprise shRNA molecules comprising one or more of SEQ ID NOs 4, 5, 6, and 12; or (¶10-12) derivatives of those sequences that can have at least 80% identity to those SEQ ID NOs. The following alignments show that WO074 SEQ ID NO 4 is 100% identical to claimed SEQ ID NO 2, WO074 SEQ ID NO 5 is 100% identical to claimed SEQ ID NO 3, and WO074 SEQ ID NOs 6 and 12 are each 95.2% identical to claimed SEQ ID NO 4. WO074 SEQ ID NOs 4 and 5 are each 21-mer. WO074 SEQ ID NOs 6 and 12 are each 20-mer:
BCB15648
(NOTE: this sequence has 7 duplicates in the database searched.
See complete list at the end of this report)
ID BCB15648 standard; DNA; 21 BP.
XX
AC BCB15648;
XX
DT 13-AUG-2015 (first entry)
XX
DE Mouse salvador (Sav1) cDNA-targeted shRNA, SEQ ID 4.
XX
KW Protein salvador homolog 1; SAV1 gene; antiinflammatory; cardiac failure;
KW cardiant; cardiovascular disease; cardiovascular-gen.;
KW diabetic cardiomyopathy; duchenne dystrophy; fibrosis; gene silencing;
KW growth-disorder-gen.; ischemia; muscular-gen.; myocardial disease;
KW myocardial infarction; necrosis; neuroprotective; rna interference;
KW short hairpin RNA; ss; therapeutic; vasotropic.
XX
OS Mus musculus.
XX
CC PN WO2015089074-A1.
XX
CC PD 18-JUN-2015.
XX
CC PF 09-DEC-2014; 2014WO-US069349.
XX
PR 09-DEC-2013; 2013US-0913715P.
XX
CC PA (BAYU ) BAYLOR COLLEGE MEDICINE.
CC PA (TEXA-) TEXAS HEART INST.
XX
CC PI Martin JF, Morikawa Y, Heallen TR, Leach J;
XX
DR WPI; 2015-35680T/46.
XX
CC PT New isolated synthetic nucleic acid composition useful for treating
CC PT individual for cardiac condition e.g. cardiovascular disease, heart
CC PT failure, myocardial infarction, ischemia, and necrosis, comprises
CC PT specific base pair sequence.
XX
CC PS Claim 1; SEQ ID NO 4; 55pp; English.
XX
CC The present invention relates to a novel isolated synthetic nucleic acid
CC composition comprising shRNA oligonucleotides (see BCB15648-BCB15656).
CC The invention further provides: (1) a method for treating an individual
CC for a cardiac condition (e.g., cardiovascular disease, cardiomyopathy,
CC heart failure, myocardial infarction, ischemia, necrosis, fibrosis, or
CC diabetic cardiomyopathy, age-related cardiomyopathy) and duchenne
CC muscular dystrophy (DMD), by providing the composition or a shRNA that
CC targets a salvador (Sav1) to the individual; and (2) a kit comprising the
CC composition. The present sequence represents a mouse Sav1 cDNA-targeted
CC shRNA, which is used in the composition of the invention for treating the
CC above-mentioned cardiac condition. Note: This sequence is described in
CC the specification as a short hairpin RNA (shRNA) but is shown as a DNA
CC sequence.
XX
SQ Sequence 21 BP; 9 A; 2 C; 8 G; 2 T; 0 U; 0 Other;
Query Match 100.0%; Score 21; Length 21;
Best Local Similarity 100.0%;
Matches 21; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AAGTACGTGAAGAAGGAGACG 21 Claimed SEQ ID NO 2
|||||||||||||||||||||
Db 1 AAGTACGTGAAGAAGGAGACG 21 WO074 SEQ ID NO 4
BCB15649
(NOTE: this sequence has 7 duplicates in the database searched.
See complete list at the end of this report)
ID BCB15649 standard; DNA; 21 BP.
XX
AC BCB15649;
XX
DT 13-AUG-2015 (first entry)
XX
DE Mouse salvador (Sav1) cDNA-targeted shRNA, SEQ ID 5.
XX
[repeated data is truncated]
CC PN WO2015089074-A1.
XX
[repeated data is truncated]
XX
CC PS Claim 1; SEQ ID NO 5; 55pp; English.
XX
[repeated data is truncated]
XX
SQ Sequence 21 BP; 4 A; 8 C; 2 G; 7 T; 0 U; 0 Other;
Query Match 100.0%; Score 21; Length 21;
Best Local Similarity 100.0%;
Matches 21; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AAGATTTACCCCTTCCTCCTG 21 Claimed SEQ ID NO 3
|||||||||||||||||||||
Db 1 AAGATTTACCCCTTCCTCCTG 21 WO074 SEQ ID NO 5
BCB15650
(NOTE: this sequence has 5 duplicates in the database searched.
See complete list at the end of this report)
ID BCB15650 standard; DNA; 20 BP.
XX
AC BCB15650;
XX
DT 13-AUG-2015 (first entry)
XX
[repeated data is truncated]
XX
CC PN WO2015089074-A1.
XX
[repeated data is truncated]
XX
CC PS Claim 1; SEQ ID NO 6; 55pp; English.
XX
[repeated data is truncated]
XX
SQ Sequence 20 BP; 3 A; 5 C; 5 G; 7 T; 0 U; 0 Other;
Query Match 95.2%; Score 20; Length 20;
Best Local Similarity 100.0%;
Matches 20; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 2 ATTCCTGACTGGCTTCAGGT 21 Claimed SEQ ID NO 4
||||||||||||||||||||
Db 1 ATTCCTGACTGGCTTCAGGT 20 WO074 SEQ ID NO 6
BCB15656
ID BCB15656 standard; DNA; 20 BP.
XX
AC BCB15656;
XX
DT 13-AUG-2015 (first entry)
XX
DE Human salvador (Sav1) cDNA-targeted shRNA, SEQ ID 12.
XX
[repeated data is truncated]
XX
OS Homo sapiens.
XX
CC PN WO2015089074-A1.
XX
[repeated data is truncated]
XX
CC PS Claim 1; SEQ ID NO 12; 55pp; English.
XX
[repeated data is truncated]
XX
SQ Sequence 20 BP; 3 A; 5 C; 5 G; 7 T; 0 U; 0 Other;
Query Match 95.2%; Score 20; Length 20;
Best Local Similarity 100.0%;
Matches 20; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 2 ATTCCTGACTGGCTTCAGGT 21 Claimed SEQ ID NO 4
||||||||||||||||||||
Db 1 ATTCCTGACTGGCTTCAGGT 20 WO074 SEQ ID NOs 9 and 12
Therefore WO074 discloses SEQ ID NOs identical to claimed SEQ ID NOs 2 and 3 and at least 80% identical to claimed SEQ ID NO 4. Those are limitations recited in Claims 1-4, 6, and 8.
Regarding Claims 6, 26-27: WO074 teaches (¶15) some embodiments wherein two or more of the nucleic acids comprising SEQ ID NOs 4-6 and 12 are present in the same vector and are regulated by the same regulatory sequence. Those are limitations of Claims 6 and 26-27.
Regarding Claims 15-16, 20, 23, 29, 31-32: Regarding the vectors, WO074 teaches (¶13) the vector encoding the nucleic acids can be a viral or nonviral vector and can be a lentiviral vector. WO074 teaches (¶18) an AAV9 vector. A vector is a kind of nucleic acid construct. Regarding the promoters, tissue-specific promoters, and cardiac troponin T promoter, WO074 teaches (¶14) expression of the nucleic acid can be regulated by a tissue- or cell-specific promoter, including a cTNT promoter. Therefore WO074 teaches limitations of Claims 15-16, 20, 23, 29, 31-32.
Regarding Claim 34, WO074 teaches (¶83) a vector that comprises a polyadenylation signal. Evidence from Wikipedia demonstrates that (§Mechanism ¶1-2, bulleted list) a polyA signal is a post-transcriptional regulatory element. Therefore WO074 teaches limitations of Claim 34.
Regarding Claim 38, WO074 teaches (¶76-78) administering shRNA to a subject including a mammalian subject. Therefore WO074 teaches limitations of Claim 38.
In addition, WO117, drawn to Hippo pathway deficiency reversing systolic heart failure post-infarction, teaches (¶12) shRNA that targets SAV1.
Regarding a sequence that is or comprises exactly claimed SEQ ID NO 4 (i.e., Claim 28): WO117 teaches (¶18, Fig. 4i) an AAV9 construct comprising three SAV1-targeting shRNAs. One of those sequences is a 22-mer that comprises claimed SEQ ID NO 4; note that WO117 does not provide a SEQ ID NO for that sequence. An annotated Fig. 4i is shown here to indicate the sequence, and an alignment to claimed SEQ ID NO 4 is shown after that:
PNG
media_image1.png
479
631
media_image1.png
Greyscale
BGD27434
ID BGD27434 standard; DNA; 22 BP.
XX
AC BGD27434;
XX
DT 02-MAY-2019 (first entry)
XX
DE Mouse SAV1 targeting shRNA sense stand # 3.
XX
KW Protein salvador homolog 1; RNA interference; SAV; SAV1 gene; Salv; WW45;
KW WWp4; cardiant; cardiovascular disease; diabetic cardiomyopathy;
KW diagnostic test; duchenne dystrophy; fibrosis; gene silencing;
KW heart disease; ischemia; myocardial disease; myocardial infarction;
KW necrosis; prophylactic to disease;
KW salvador family WW domain containing protein 1 gene; salvador homolog 1;
KW short hairpin RNA; ss; therapeutic.
XX
OS Mus sp.
XX
CC PN WO2019051117-A1.
XX
CC PD 14-MAR-2019.
XX
CC PF 06-SEP-2018; 2018WO-US049792.
XX
PR 06-SEP-2017; 2017US-0554627P.
XX
CC PA (BAYU ) BAYLOR COLLEGE MEDICINE.
XX
CC PI Martin JF, Leach J;
XX
DR WPI; 2019-242265/22.
XX
CC PT Treating an individual for a cardiac condition, such as cardiovascular
CC PT disease, cardiomyopathy and heart failure, involves providing an
CC PT effective amount of a Park2 nucleic acid composition and/or Park2
CC PT polypeptide composition to individual.
XX
CC PS Example 1; Fig 4i; 123pp; English.
XX
CC The invention relates to a novel method and composition, used for
CC treating an individual for a cardiac condition. The cardiac condition in
CC the individual causes the individual to be in need of cardiomyocyte
CC renewal, and the heart of the individual may have cardiomyocyte
CC apoptosis, necrosis, and/or autophagy. The composition is used for
CC preventing or diagnosed as having a cardiac condition such as
CC cardiovascular disease, cardiomyopathy, heart failure, myocardial
CC infarction, ischemia, fibrosis, or diabetic cardiomyopathy, age-related
CC cardiomyopathy, and individual has Duchenne muscular dystrophy. The
CC composition may be provided to the individual systemically, locally
CC (including to the heart), or both. The method enables to treat an
CC individual for a cardiac condition, which reduces severity or delays
CC onset of one or more cardiac conditions in a mammal. The present sequence
CC represents a mouse salvador homolog 1 (SAV1/Salv/SAV/WW45/WWP4/salvador
CC family WW domain containing protein 1) targeting shRNA, used in the
CC composition for treating an individual for a cardiac condition. Note:
CC This sequence is described in the specification as a shRNA but is shown
CC as a DNA sequence.
XX
SQ Sequence 22 BP; 4 A; 6 C; 5 G; 7 T; 0 U; 0 Other;
Query Match 100.0%; Score 21; Length 22;
Best Local Similarity 100.0%;
Matches 21; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AATTCCTGACTGGCTTCAGGT 21 Claimed SEQ ID NO 4
|||||||||||||||||||||
Db 2 AATTCCTGACTGGCTTCAGGT 22 WO117 SAV1-targeting shRNA sequence (Fig. 4i)
That alignment indicates that the WO117 sequence (which will be referred to “SEQ ID NO 4i”) has 100% identity to—and therefore has—the sequence set forth in claimed SEQ ID NO 4. Furthermore, WO117 teaches (¶136) the RNA duplex of their invention can comprise two complementary single-stranded RNAs that can be various lengths including 20-, 21-, or 22-mer. Therefore WO117 teaches some limitations of Claim 28.
Regarding limitations of Claim 30, WO117 teaches (¶175, Fig. 4i) an AAV9 comprising a triple shRNA construct with flanking miR30 sequences. That indicates (and Fig. 4i shows) the construct comprises sequences encoding a 5’ miR-30 sequence and a 3’ miR-30 sequence. Those are limitations of Claim 30.
Regarding Claim 35 (i.e., the WPRE element), WO117 Fig. 4i (above) shows including that element in the nucleic acid construct. Furthermore, Wikipedia, drawn to a description of the WPRE, teaches that the WPRE creates a tertiary structure that enhances expression and that a WPRE is commonly used in molecular biology to increase expression of genes delivered by viral vectors.
Therefore, in view of Plouffe, He, and Choi’s teachings about SAV1 negatively regulating YAP in the Hippo pathway; Lee and Zhou’s teachings about SAV1 downregulation resulting in YAP upregulation; Watt and Watt 2015’s teachings about increasing YAP to increase muscle regeneration and satellite cell proliferation; and He’s teachings about upregulating YAP to regulate angiogenesis (including to treat limb ischemia), it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use WO074 and WO113’s methods of inhibiting SAV1 using SAV1-targeting shRNAs comprising WO074 SEQ ID NOs 4 and 5 and WO117 SEQ ID NO 4i. One would have used those teachings and methods of Watt, Watt 2015, WO074, and WO117 (including intramuscular injection of nucleic acid constructs encoding the shRNAs comprising specific SEQ ID NOs) to inhibit SAV1 and thereby increase YAP for the benefits of increasing YAP to increase angiogenesis in skeletal muscle suffering from limb ischemia and thereby treat the condition, regenerate muscle cells in aged skeletal muscle, and enhance satellite cell proliferation.
One would have been motivated to do so with a reasonable expectation of success because the teachings of Plouffe (Fig. 1), He (Fig. 1), Choi (§Abstract, Fig. 2), Lee (§Abstract), Zhou (§ROLE OF YAP IN MOUSE CARDIOVASCULAR DEVELOPMENT) indicate that downregulating SAV1 upregulates YAP; because Watt and Watt 2015 indicate YAP (Watt 2015 §YAP promotes hypertrophy via TEAD transcription factors) promotes hypertrophy, (Watt §Yap and Taz expression in skeletal muscle ¶1) supports muscle regeneration, (Watt §The functional role of Yap and Taz during satellite cell activation ¶1) enhances satellite cell proliferative dynamics and suggest (Watt §Yap and Taz expression in skeletal muscle ¶1) increasing YAP could treat sarcopenia; because He and Choi teach YAP is necessary for angiogenesis and He suggests (§Hippo/YAP pathway and angiogenesis) upregulating YAP to increase angiogenesis and treat ischemic disease; and because WO074 and WO117 teach methods and shRNA constructs for inhibiting SAV1. In addition, Watt 2015 indicates it is routine and conventional to administer shRNA to skeletal muscle. It would have been a simple matter to deliver to skeletal muscle by known methods the shRNAs disclosed in WO074 and WO117 to inhibit SAV1. It would have been obvious to use any or all of the SAV1-targeting shRNAs of WO074 and WO117 because the references teach only a handful of shRNAs and using any of them would have been obvious. It would have been obvious to encode any number of those shRNAs on a single nucleic acid construct under the control of any promoter because WO074 teaches doing so and an artisan would have wanted to maximize shRNA expression. It would have been obvious to encode the shRNAs on the AAV9 shown in WO117 Fig. 4i because WO117 teaches (¶175) AAV9 is muscle-tropic. Then, an artisan would have expected the shRNA or shRNAs to be expressed in the muscle cells.
Therefore the limitations of Claims 1-4, 6, 8-9, 11, 15-16, 20, 23, 26-32, 34, 38-39, and 42 would have been obvious in view of Plouffe, He, Choi, Lee, Zhou, Watt, Watt 2015, WO074, and WO117.
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 the AAV comprising SEQ ID NOs 2, 3, and/or 4 of Plouffe, He, Choi, Lee, Zhou, Watt, Watt 2015, WO074, and WO117 with the WPRE of WO117 and Wikipedia for the benefit of increasing expression of genes delivered by viral vectors. One would have been motivated to do so with a reasonable expectation of success because WO117 shows (Fig. 4i) a nucleic acid construct comprising a WPRE and Wikipedia teaches using a WPRE to enhance expression is commonly used in the art of molecular biology.
Therefore the limitations of Claims 1-4, 6, 8-9, 11, 15-16, 20, 23, 26-32, 34-35, 38-39, and 42 would have been obvious in view of Plouffe, He, Choi, Lee, Zhou, Watt, Watt 2015, WO074, WO117 and Wikipedia.
Claim(s) 1-4, 6, 8-9, 11, 15-16, 20, 23, 26-32, 34-36, 38-39, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Plouffe, He, Choi, Lee, Zhou, Watt, Watt 2015, WO074, WO117, and Wikipedia as applied to Claims 1-4, 6, 8-9, 11, 15-16, 20, 23, 36-32, 34-35, 38-39, and 42 in the 103 rejection above, and further in view of US Patent Application Publication No. US 2020/0148745 (published 14 May 2020, “App745”). All references are of record. This rejection is maintained.
The teachings of Plouffe, He, Choi, Lee, Zhou, Watt, Watt 2015, WO074, WO117, and Wikipedia as applicable to Claim(s) 1-4, 6, 8-9, 11, 15-16, 20, 23, 36-32, 34, 38-39, and 42 have been described above. Plouffe, He, Choi, Lee, Zhou, Watt, Watt 2015, WO074, WO117, and Wikipedia make obvious methods of increasing angiogenesis in skeletal muscle, the method comprising delivering to skeletal muscle cells an effective amount of a composition comprising at a nucleic acid construct comprising nucleic acids having the nt sequence of SEQ ID NO 2, SEQ ID NO 3, and SEQ ID NO 4; wherein the nucleic acids are operably linked to a promoter, wherein the nucleic acid construct is comprised in an AAV, and wherein the AAV comprises a post-transcriptional regulatory element.
Plouffe, He, Choi, Lee, Zhou, Watt, Watt 2015, WO074, WO117, and Wikipedia do not teach the AAV comprises 5’ and 3’ inverted terminal repeat sequences (ITRs).
Regarding Claim 36: However, App475, drawn to AAV vectors, teaches (¶99) functional flanking ITRs are necessary for rescue, replication, and packaging of an AAV virion, and an AAV vector is defined to include those sequences.
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 the AAV comprising SEQ ID NOs 2, 3, and/or 4 of Plouffe, He, Choi, Lee, Zhou, Watt, Watt 2015, WO074, and WO117 with the flanking ITRs of App475 for the benefit of packaging an AAV virion. One would have been motivated to do so with a reasonable expectation of success because the teachings of App475 indicate that it was routine and conventional to include such flanking ITRs in any AAV vector. Note that a person of ordinary skill would understand that “flanking ITRs” are 5’ and 3’ ITRs. Therefore the limitations of Claim 36 would have been obvious in view of Plouffe, He, Choi, Lee, Zhou, Watt, Watt 2015, WO074, WO117, Wikipedia, and App475.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 6, 8-9, 11, 15-16, 20, 23, 26-32, 34-36, 38-39, and 42 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 Plouffe (et al. 2015. Disease implications of the Hippo/YAP pathway. Trends Molec. Med. 21[4]:212-222, “Plouffe”), He (et al. 2017. The role of Hippo/yes-associated protein signalling in vascular remodelling associated with cardiovascular disease. Brit. J. Pharmacol. 175:1354-1361, “He”), Choi (et al. 2015. Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2. Nat. Comm. 6:6943, “Choi”), Lee (et al. 2010. The Hippo–Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. PNAS 107[8]:8249-8253, “Lee”), Zhou (2014. An emerging role for Hippo-YAP signaling in cardiovascular development. J. Biomed. Res. 28[4]:251-254, “Zhou”), Watt (et al. April 2019. Author manuscript of The Hippo Signaling Pathway in the Regulation of Skeletal Muscle Mass and Function. Exerc. Sport Sci. Rev. 46[2]:92-96, “Watt”, published version of record on IDS), Watt (et al. 2015. The Hippo pathway effector YAP is a critical regulator of skeletal muscle fibre size. Nat. Comm. 6:6048, “Watt 2015”), International Publication Number WO 2015/089074 (published 18 June 2015, “WO074” of record on IDS) as evidenced by Wikipedia (“Post transcriptional regulation”. page archived 25 October 2020. Available at Wikipedia.org. Accessed on 11 March 2026, “Wikipedia”), and International Publication Number WO 2019/051117 (published 14 March 2019, “WO117”, of record on IDS), Wikipedia ("WHP Posttransciptional Response Element". page archived 09 March 2018. Available at Wikipedia.org. Accessed on 11 March 2026, “Wikipedia”), and US Patent Application Publication No. US 2020/0148745 (published 14 May 2020, “App745”). All references are of record. This rejection is maintained.
US Patent
Abbreviation
Claims
US 9,732,345
US345
1-24
US 10,119,141
US141
1-17
US 11,459,565
US565
1-19
US 11,981,895
US895
1-21
US 12,480,120
US120
1-18
The instant claims are directed to methods of increasing angiogenesis, regenerating myofibers, inducing proliferation of satellite cells, and treating limb ischemia in skeletal muscle, the method comprising delivering to skeletal muscle cells an effective amount of a composition comprising at a nucleic acid construct comprising nucleic acids having the nt sequences of any or all of SEQ ID NO 2, SEQ ID NO 3, and/or SEQ ID NO 4 or 80% identity to them; wherein the nucleic acids are operably linked to a promoter (including a single promoter regulating all three) that can be a tissue-specific promoter including a cardiac troponin T promoter, wherein the inhibitor nucleic acid can be shRNA, wherein the nucleotide sequence(s) can be comprised in a vector or in a nucleic acid construct, wherein the nucleic acid construct can comprise sequences encoding 3’ and 5’ miR-30 sequences and/or the construct can be comprised in a viral vector that can be an AAV or lentivirus, and wherein the AAV can comprise 5’ and 3’ ITR or a post-transcriptional regulatory element that can be WPRE. The instant claims also recite the method wherein the composition is administered to a mammalian subject, wherein the skeletal muscle is ischemic, atrophied, or has suffered a traumatic injury, or where when the mammalian subject has a condition that can be limb ischemia, PVD, or sarcopenia.
The patented claims are directed to (US345, US565) methods of treating an individual in need of treatment for a cardiac condition, comprising providing synthetic nucleic acids comprising specific SEQ ID NOs or nucleic acids comprising at least 80% identity to certain SEQ ID NOs, wherein the nucleic acid can be in a vector and can be regulated by a cTNT promoter, wherein two or more of the SEQ ID NOs can be on the same vector and can be regulated by the same regulatory sequence; and (US141, US565, US895, US120) isolated synthetic nucleic acid compositions comprising specific SEQ ID NOs or nucleic acids comprising at least 80% identity to certain SEQ ID NOs, wherein the nucleic acid can be in a vector and can be regulated by a cTNT promoter, wherein two or more of the SEQ ID NOs can be on the same vector and can be regulated by the same regulatory sequence. The following shows select sequence alignments demonstrating that the patented SEQ ID NOs are identical to the instantly claimed SEQ ID NOs. Note that SEQ ID NOs 10, 11, and 12 are identical across the issued patents. Only one alignment is shown per instantly claimed SEQ ID NO. Note that the alignment results below show the issued patent for Application No. 15/102593 is US9708613 whereas the actual issue number is US9732345.
RESULT 1
US-15-102-593-10
(NOTE: this sequence has 17 duplicates in the database searched.
See complete list at the end of this report)
Sequence 10, US/15102593
Patent No. 9708613
GENERAL INFORMATION
APPLICANT: Martin, James F.
APPLICANT: Yuka, Morikawa
APPLICANT: Todd, Heallen Ryan
APPLICANT: Leach, John
TITLE OF INVENTION: HIPPO AND DYSTROPHIN COMPLEX SIGNALING IN CARDIOMYOCYTE RENEWAL
FILE REFERENCE: BAYM.P0129US
CURRENT APPLICATION NUMBER: US/15/102,593
CURRENT FILING DATE: 2016-06-08
PRIOR APPLICATION NUMBER: PCT/US2014/069349
PRIOR FILING DATE: 2014-12-09
PRIOR APPLICATION NUMBER: 61/913,715
PRIOR FILING DATE: 2013-12-09
NUMBER OF SEQ ID NOS: 12
SEQ ID NO 10
LENGTH: 21
TYPE: DNA
ORGANISM: Homo sapiens
Query Match 100.0%; Score 21; Length 21;
Best Local Similarity 100.0%;
Matches 21; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AAGTACGTGAAGAAGGAGACG 21 claimed SEQ ID NO 2
|||||||||||||||||||||
Db 1 AAGTACGTGAAGAAGGAGACG 21
RESULT 1
US-15-102-593-11
(NOTE: this sequence has 17 duplicates in the database searched.
See complete list at the end of this report)
Sequence 11, US/15102593
Patent No. 9708613
GENERAL INFORMATION
APPLICANT: Martin, James F.
APPLICANT: Yuka, Morikawa
APPLICANT: Todd, Heallen Ryan
APPLICANT: Leach, John
TITLE OF INVENTION: HIPPO AND DYSTROPHIN COMPLEX SIGNALING IN CARDIOMYOCYTE RENEWAL
FILE REFERENCE: BAYM.P0129US
CURRENT APPLICATION NUMBER: US/15/102,593
CURRENT FILING DATE: 2016-06-08
PRIOR APPLICATION NUMBER: PCT/US2014/069349
PRIOR FILING DATE: 2014-12-09
PRIOR APPLICATION NUMBER: 61/913,715
PRIOR FILING DATE: 2013-12-09
NUMBER OF SEQ ID NOS: 12
SEQ ID NO 11
LENGTH: 21
TYPE: DNA
ORGANISM: Homo sapiens
Query Match 100.0%; Score 21; Length 21;
Best Local Similarity 100.0%;
Matches 21; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AAGATTTACCCCTTCCTCCTG 21 claimed SEQ ID NO 3
|||||||||||||||||||||
Db 1 AAGATTTACCCCTTCCTCCTG 21
RESULT 25
US-15-102-593-12
(NOTE: this sequence has 17 duplicates in the database searched.
See complete list at the end of this report)
Sequence 12, US/15102593
Patent No. 9708613
GENERAL INFORMATION
APPLICANT: Martin, James F.
APPLICANT: Yuka, Morikawa
APPLICANT: Todd, Heallen Ryan
APPLICANT: Leach, John
TITLE OF INVENTION: HIPPO AND DYSTROPHIN COMPLEX SIGNALING IN CARDIOMYOCYTE RENEWAL
FILE REFERENCE: BAYM.P0129US
CURRENT APPLICATION NUMBER: US/15/102,593
CURRENT FILING DATE: 2016-06-08
PRIOR APPLICATION NUMBER: PCT/US2014/069349
PRIOR FILING DATE: 2014-12-09
PRIOR APPLICATION NUMBER: 61/913,715
PRIOR FILING DATE: 2013-12-09
NUMBER OF SEQ ID NOS: 12
SEQ ID NO 12
LENGTH: 20
TYPE: DNA
ORGANISM: Homo sapiens
Query Match 95.2%; Score 20; Length 20;
Best Local Similarity 100.0%;
Matches 20; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 2 ATTCCTGACTGGCTTCAGGT 21 claimed SEQ ID NO 4
||||||||||||||||||||
Db 1 ATTCCTGACTGGCTTCAGGT 20
All claim sets are directed to methods or compositions comprising the exact same SEQ ID NOs.
The issued claims do not recite using the SEQ ID NOs to treat skeletal muscle-related conditions; however, using the patented SEQ ID NOs to treat those conditions would have been obvious in view of the prior art of Plouffe (§Abstract, Fig. 1; §The Hippo pathway in intestinal regeneration, §The Hippo pathway in cardiomyocyte regeneration), He (§Introduction ¶2, §Components of the Hippo/YAP pathway, Fig. 1; §Hippo/YAP pathway and angiogenesis), Choi (§Abstract, Fig. 2), Lee (§Abstract), Zhou (§ROLE OF YAP IN MOUSE CARDIOVASCULAR DEVELOPMENT), Watt (§The Hippo signaling pathway, Fig. 1, §Introduction ¶1, §Yap and Taz expression in skeletal muscle, §The functional role of Yap and Taz during satellite cell activation, §Yap and Taz promote muscle growth via Tead in Post-natal muscle fibers), Watt 2015 (§Abstract, §YAP is required to maintain basal skeletal myofibre size, §YAP promotes hypertrophy via TEAD transcription factors, Figs. 1a and 3a), WO074 (¶8, ¶51, ¶9, ¶10-12, ¶15, ¶13, ¶18, ¶14, ¶83, ¶76-78), WO117 (¶12, ¶18, Fig. 4i, ¶136, ¶175, Fig. 4i), Wikipedia, and App745 (¶99) for the benefits of increasing angiogenesis, regenerating myofibers, inducing proliferation of satellite cells, and treating limb ischemia in skeletal muscle, as taught in the prior art. One would have been motivated to do so with a reasonable expectation of success because the cited prior art teaches that increasing YAP induces the outcomes of increasing angiogenesis, regenerating myofibers, inducing proliferation of satellite cells, and treating limb ischemia in skeletal muscle, and also teaches that it is possible to increase YAP by inhibiting a Hippo pathway component upstream of YAP, namely SAV1. The cited prior art also teaches benefits of including the various elements (e.g., the WPRE element increases gene expression). Therefore it would have been obvious to use the patented SEQ ID NOs to inhibit SAV1, thereby increasing YAP and inducing the outcomes of increasing angiogenesis, regenerating myofibers, inducing proliferation of satellite cells, and treating limb ischemia in skeletal muscle. Therefore the instant claims would have been obvious in view of the patented claims and the cited prior art. In addition, it would not be possible to use the instant claims without the compositions of the patented claims.
Claims 1-4, 6, 8-9, 11, 15-16, 20, 23, 26-32, 34-36, 38-39, and 42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. US 11,944,671 (“US671”) in view of Plouffe, He, Choi, Lee, Zhou, Watt, Watt 2015, WO074, WO117, Wikipedia, App745, and Leduc-Gaudet (et al. April 2019. Parkin overexpression protects from ageing-related loss of muscle mass and strength. J. Physiol. 597.7:1975–1991, “Leduc-Gaudet”). All references are of record. This rejection is maintained.
The instant claims are directed to methods of increasing angiogenesis, regenerating myofibers, inducing proliferation of satellite cells, and treating limb ischemia in skeletal muscle, the method comprising delivering to skeletal muscle cells an effective amount of a composition comprising at a nucleic acid construct comprising nucleic acids having the nt sequences of any or all of SEQ ID NO 2, SEQ ID NO 3, and/or SEQ ID NO 4 or 80% identity to them; wherein the nucleic acids are operably linked to a promoter (including a single promoter regulating all three) that can be a tissue-specific promoter including a cardiac troponin T promoter, wherein the inhibitor nucleic acid can be shRNA, wherein the nucleotide sequence(s) can be comprised in a vector or in a nucleic acid construct, wherein the nucleic acid construct can comprise sequences encoding 3’ and 5’ miR-30 sequences and/or the construct can be comprised in a viral vector that can be an AAV or lentivirus, and wherein the AAV can comprise 5’ and 3’ ITR or a post-transcriptional regulatory element that can be WPRE. The instant claims also recite the method wherein the composition is administered to a mammalian subject, wherein the skeletal muscle is ischemic, atrophied, or has suffered a traumatic injury, or where when the mammalian subject has a condition that can be limb ischemia, PVD, or sarcopenia.
The patented claims are directed to methods of treating an individual for heart failure, the method comprising administering to the individual an effective amount of a Park2 nucleic acid and an shRNA that targets SAV1, wherein the shRNA comprises a sequence selected from the group consisting of SEQ ID NO 27, 28, and 29.
The following shows select sequence alignments demonstrating that the patented SEQ ID NOs are identical to the instantly claimed SEQ ID NOs:
US-16-644-435-27
Filing date in PALM: 2020-03-04
Sequence 27, US/16644435
Patent No. 11944671
GENERAL INFORMATION
APPLICANT: BAYLOR COLLEGE OF MEDICINE
TITLE OF INVENTION: HIPPO PATHWAY DEFICIENCY REVERSES SYSTOLIC HEART FAILURE
TITLE OF INVENTION: POST-INFARCTION
FILE REFERENCE: BAYM.P0240US-1001116313
CURRENT APPLICATION NUMBER: US/16/644,435
CURRENT FILING DATE: 2020-03-04
PRIOR APPLICATION NUMBER: PCT/US2018/049792
PRIOR FILING DATE: 2018-09-06
PRIOR APPLICATION NUMBER: 62/554,627
PRIOR FILING DATE: 2017-09-06
NUMBER OF SEQ ID NOS: 38
SEQ ID NO 27
LENGTH: 21
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
Oligonucleotide
Query Match 100.0%; Score 21; Length 21;
Best Local Similarity 100.0%;
Matches 21; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AAGTACGTGAAGAAGGAGACG 21 claimed SEQ ID NO 2
|||||||||||||||||||||
Db 1 AAGTACGTGAAGAAGGAGACG 21
US-16-644-435-28
Filing date in PALM: 2020-03-04
Sequence 28, US/16644435
Patent No. 11944671
GENERAL INFORMATION
APPLICANT: BAYLOR COLLEGE OF MEDICINE
TITLE OF INVENTION: HIPPO PATHWAY DEFICIENCY REVERSES SYSTOLIC HEART FAILURE
TITLE OF INVENTION: POST-INFARCTION
FILE REFERENCE: BAYM.P0240US-1001116313
CURRENT APPLICATION NUMBER: US/16/644,435
CURRENT FILING DATE: 2020-03-04
PRIOR APPLICATION NUMBER: PCT/US2018/049792
PRIOR FILING DATE: 2018-09-06
PRIOR APPLICATION NUMBER: 62/554,627
PRIOR FILING DATE: 2017-09-06
NUMBER OF SEQ ID NOS: 38
SEQ ID NO 28
LENGTH: 21
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
oligonucleotide
Qy 1 AAGATTTACCCCTTCCTCCTG 21 claimed SEQ ID NO 3
|||||||||||||||||||||
Db 1 AAGATTTACCCCTTCCTCCTG 21
US-16-644-435-29
Filing date in PALM: 2020-03-04
Sequence 29, US/16644435
Patent No. 11944671
GENERAL INFORMATION
APPLICANT: BAYLOR COLLEGE OF MEDICINE
TITLE OF INVENTION: HIPPO PATHWAY DEFICIENCY REVERSES SYSTOLIC HEART FAILURE
TITLE OF INVENTION: POST-INFARCTION
FILE REFERENCE: BAYM.P0240US-1001116313
CURRENT APPLICATION NUMBER: US/16/644,435
CURRENT FILING DATE: 2020-03-04
PRIOR APPLICATION NUMBER: PCT/US2018/049792
PRIOR FILING DATE: 2018-09-06
PRIOR APPLICATION NUMBER: 62/554,627
PRIOR FILING DATE: 2017-09-06
NUMBER OF SEQ ID NOS: 38
SEQ ID NO 29
LENGTH: 20
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
Oligonucleotide
Qy 2 ATTCCTGACTGGCTTCAGGT 21 claimed SEQ ID NO 4
||||||||||||||||||||
Db 1 ATTCCTGACTGGCTTCAGGT 20
Both claim sets are directed to methods or compositions comprising the exact same SEQ ID NOs.
The issued claims do not recite using the SEQ ID NOs to treat skeletal muscle-related conditions; however, using the patented methods and SEQ ID NOs to treat those conditions would have been obvious in view of the prior art of Plouffe (§Abstract, Fig. 1; §The Hippo pathway in intestinal regeneration, §The Hippo pathway in cardiomyocyte regeneration), He (§Introduction ¶2, §Components of the Hippo/YAP pathway, Fig. 1; §Hippo/YAP pathway and angiogenesis), Choi (§Abstract, Fig. 2), Lee (§Abstract), Zhou (§ROLE OF YAP IN MOUSE CARDIOVASCULAR DEVELOPMENT), Watt (§The Hippo signaling pathway, Fig. 1, §Introduction ¶1, §Yap and Taz expression in skeletal muscle, §The functional role of Yap and Taz during satellite cell activation, §Yap and Taz promote muscle growth via Tead in Post-natal muscle fibers), Watt 2015 (§Abstract, §YAP is required to maintain basal skeletal myofibre size, §YAP promotes hypertrophy via TEAD transcription factors, Figs. 1a and 3a), WO074 (¶8, ¶51, ¶9, ¶10-12, ¶15, ¶13, ¶18, ¶14, ¶83, ¶76-78), WO117 (¶12, ¶18, Fig. 4i, ¶136, ¶175, Fig. 4i), Wikipedia, and App745 (¶99). In addition, WO117 teaches (¶27) Park2 is necessary for cardiac muscle regeneration and Leduc-Gaudet teaches (§Abstract) overexpressing PARK2 (called by its protein name, Parkin in the reference) increases muscle mass and fiber size. One would have used the patented methods in view of the teachings of the cited prior art for the benefits of increasing angiogenesis, regenerating myofibers, inducing proliferation of satellite cells, and treating limb ischemia in skeletal muscle, as taught in the prior art. One would have been motivated to do so with a reasonable expectation of success because the cited prior art teaches that increasing YAP induces the outcomes of increasing angiogenesis, regenerating myofibers, inducing proliferation of satellite cells, and treating limb ischemia in skeletal muscle, and also teaches that it is possible to increase YAP by inhibiting a Hippo pathway component upstream of YAP, namely SAV1. The cited prior art also teaches benefits of including the various elements (e.g., the WPRE element increases gene expression) and (Leduc-Gaudet) expressing PARK2 in muscles. Therefore it would have been obvious to use the patented methods and SEQ ID NOs to inhibit SAV1, thereby increasing YAP and inducing the outcomes of increasing angiogenesis, regenerating myofibers, inducing proliferation of satellite cells, and treating limb ischemia in skeletal muscle. Therefore the instant claims would have been obvious in view of the patented claims and the cited prior art. In addition, it would not be possible to use the instant claims without the compositions of the patented claims.
Claims 1-4, 6, 8-9, 11, 15-16, 20, 23, 26-32, 34-36, 38-39, and 42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 7-8, 14-15, 17, 19, 25-27, 29, 30, 33, 35, 43-44 of copending Application No. 18/876035 (“App035”) in view of Plouffe, He, Choi, Lee, Zhou, Watt, Watt 2015, WO074, WO117, and Wikipedia. All references are of record. This rejection is maintained.
The instant claims are directed to methods of increasing angiogenesis, regenerating myofibers, inducing proliferation of satellite cells, and treating limb ischemia in skeletal muscle, the method comprising delivering to skeletal muscle cells an effective amount of a composition comprising at a nucleic acid construct comprising nucleic acids having the nt sequences of any or all of SEQ ID NO 2, SEQ ID NO 3, and/or SEQ ID NO 4 or 80% identity to them; wherein the nucleic acids are operably linked to a promoter (including a single promoter regulating all three) that can be a tissue-specific promoter including a cardiac troponin T promoter, wherein the inhibitor nucleic acid can be shRNA, wherein the nucleotide sequence(s) can be comprised in a vector or in a nucleic acid construct, wherein the nucleic acid construct can comprise sequences encoding 3’ and 5’ miR-30 sequences and/or the construct can be comprised in a viral vector that can be an AAV or lentivirus, and wherein the AAV can comprise 5’ and 3’ ITR or a post-transcriptional regulatory element that can be WPRE. The instant claims also recite the method wherein the composition is administered to a mammalian subject, wherein the skeletal muscle is ischemic, atrophied, or has suffered a traumatic injury, or where when the mammalian subject has a condition that can be limb ischemia, PVD, or sarcopenia.
The copending App035 claims are directed to methods of improving systolic function, reducing arrhythmia, promoting capillary formation, and treating/preventing/reducing risk of arrhythmia in a human patient, the method comprising delivering to heart tissue an effective amount of a composition comprising at a nucleic acid construct comprising nucleic acids having the nt sequences of any or all of SEQ ID NO 2, SEQ ID NO 3, and/or SEQ ID NO 4 or 80% identity to them; wherein the nucleic acids are operably linked to a promoter (including a single promoter regulating all three) that can be a tissue-specific promoter, wherein the inhibitor nucleic acid can be shRNA, wherein the nucleotide sequence(s) can be comprised in a vector or in a nucleic acid construct, wherein the nucleic acid construct can comprise sequences encoding 3’ and 5’ miR-30 sequences and/or the construct can be comprised in a viral vector that can be an AAV or lentivirus, and wherein the AAV can comprise 5’ and 3’ ITR or a post-transcriptional regulatory element. The copending claims also recite the method wherein the composition is administered to a human subject who has experienced or is at risk for myocardial infarction.
The following shows select sequence alignments demonstrating that the copending SEQ ID NOs are identical to the instantly claimed SEQ ID NOs:
US-18-876-035-2
Filing date in PALM: 2024-12-17
Sequence 2, US/18876035
Publication No. US20250283080A1
GENERAL INFORMATION
APPLICANT: Baylor College of Medicine (en)
TITLE OF INVENTION: GENE THERAPY OF HIPPO SIGNALING IMPROVES HEART FUNCTION IN A CLINICALLY RELEVANT MODEL (en)
FILE REFERENCE: BAYM.P0372WO
CURRENT APPLICATION NUMBER: US/18/876,035
CURRENT FILING DATE: 2024-12-17
NUMBER OF SEQ ID NOS: 4
SEQ ID NO 2
LENGTH: 21
TYPE: DNA
FEATURE:
NAME/KEY: source
LOCATION: 1..21
QUALIFIERS: mol_type = other DNA
organism = synthetic construct
Qy 1 AAGTACGTGAAGAAGGAGACG 21 claimed SEQ ID NO 2
|||||||||||||||||||||
Db 1 AAGTACGTGAAGAAGGAGACG 21
US-18-876-035-3
Filing date in PALM: 2024-12-17
Sequence 3, US/18876035
Publication No. US20250283080A1
GENERAL INFORMATION
APPLICANT: Baylor College of Medicine (en)
TITLE OF INVENTION: GENE THERAPY OF HIPPO SIGNALING IMPROVES HEART FUNCTION IN A CLINICALLY RELEVANT MODEL (en)
FILE REFERENCE: BAYM.P0372WO
CURRENT APPLICATION NUMBER: US/18/876,035
CURRENT FILING DATE: 2024-12-17
NUMBER OF SEQ ID NOS: 4
SEQ ID NO 3
LENGTH: 21
TYPE: DNA
FEATURE:
NAME/KEY: source
LOCATION: 1..21
QUALIFIERS: mol_type = other DNA
organism = synthetic construct
Qy 1 AAGATTTACCCCTTCCTCCTG 21 claimed SEQ ID NO 3
|||||||||||||||||||||
Db 1 AAGATTTACCCCTTCCTCCTG 21
US-18-876-035-4
Filing date in PALM: 2024-12-17
Sequence 4, US/18876035
Publication No. US20250283080A1
GENERAL INFORMATION
APPLICANT: Baylor College of Medicine (en)
TITLE OF INVENTION: GENE THERAPY OF HIPPO SIGNALING IMPROVES HEART FUNCTION IN A CLINICALLY RELEVANT MODEL (en)
FILE REFERENCE: BAYM.P0372WO
CURRENT APPLICATION NUMBER: US/18/876,035
CURRENT FILING DATE: 2024-12-17
NUMBER OF SEQ ID NOS: 4
SEQ ID NO 4
LENGTH: 21
TYPE: DNA
FEATURE:
NAME/KEY: source
LOCATION: 1..21
QUALIFIERS: mol_type = other DNA
organism = synthetic construct
Qy 2 ATTCCTGACTGGCTTCAGGT 21 claimed SEQ ID NO 4
||||||||||||||||||||
Db 1 ATTCCTGACTGGCTTCAGGT 20
Both claim sets are directed to methods comprising the exact same SEQ ID NOs.
The copending claims do not recite using the SEQ ID NOs to treat skeletal muscle-related conditions; however, using the patented methods and SEQ ID NOs to treat those conditions would have been obvious in view of the prior art of Plouffe (§Abstract, Fig. 1; §The Hippo pathway in intestinal regeneration, §The Hippo pathway in cardiomyocyte regeneration), He (§Introduction ¶2, §Components of the Hippo/YAP pathway, Fig. 1; §Hippo/YAP pathway and angiogenesis), Choi (§Abstract, Fig. 2), Lee (§Abstract), Zhou (§ROLE OF YAP IN MOUSE CARDIOVASCULAR DEVELOPMENT), Watt (§The Hippo signaling pathway, Fig. 1, §Introduction ¶1, §Yap and Taz expression in skeletal muscle, §The functional role of Yap and Taz during satellite cell activation, §Yap and Taz promote muscle growth via Tead in Post-natal muscle fibers), Watt 2015 (§Abstract, §YAP is required to maintain basal skeletal myofibre size, §YAP promotes hypertrophy via TEAD transcription factors, Figs. 1a and 3a), WO074 (¶8, ¶51, ¶9, ¶10-12, ¶15, ¶13, ¶18, ¶14, ¶83, ¶76-78), WO117 (¶12, ¶18, Fig. 4i, ¶136, ¶175, Fig. 4i), and Wikipedia. One would have used the copending methods in view of the teachings of the cited prior art for the benefits of increasing angiogenesis, regenerating myofibers, inducing proliferation of satellite cells, and treating limb ischemia in skeletal muscle, as taught in the prior art. One would have been motivated to do so with a reasonable expectation of success because the cited prior art teaches that increasing YAP induces the outcomes of increasing angiogenesis, regenerating myofibers, inducing proliferation of satellite cells, and treating limb ischemia in skeletal muscle, and also teaches that it is possible to increase YAP by inhibiting a Hippo pathway component upstream of YAP, namely SAV1. The cited prior art also teaches benefits of including the various elements (e.g., the WPRE element increases gene expression). Therefore it would have been obvious to use the copending methods and SEQ ID NOs to inhibit SAV1, thereby increasing YAP and inducing the outcomes of increasing angiogenesis, regenerating myofibers, inducing proliferation of satellite cells, and treating limb ischemia in skeletal muscle. Therefore the instant claims would have been obvious in view of the copending claims and the cited prior art. In addition, it would not be possible to use the instant claims without the compositions of the copending claims.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments, see Remarks pp. 8-11, filed 03 August 2026, with respect to the Written Description rejections have been fully considered and are persuasive as they pertain to the amended claims. The arguments on p. 9, pertaining to the dependent claims, are considered persuasive. The Written Description rejection has been withdrawn.
The arguments pertaining to the 112(b) rejections have been fully considered and are persuasive.
Arguments that are no longer relevant are not addressed.
Applicant's arguments against the 103 and NSDP rejections, filed 03 August 2026, have been fully considered but they are not persuasive. Note that the first full ¶ on each page of Remarks is cited as ¶1 and a first partial ¶ on a page is called ¶0 (or simply referred to as the ¶# from the preceding page).
103
Applicant argues (pp. 11-18) against the 103 rejections. First Applicant argues (p. 11 ¶2) the invention isn’t obvious because the references demonstrate that Hippo signaling is a complex, highly context-dependent signaling network, the biological effects of which cannot be predicted simply from the position of a protein within the signaling cascade. Applicant argues that the references caution that upstream components may function independently of YAP/TAZ and upstream regulation of YAP is incompletely understood. Applicant argues (p. 12 ¶1 and ¶4, p. 13 ¶4, p. 14 ¶2) Hippo signaling isn’t necessarily a linear pathway whose downstream consequences are predictable, and the pathway isn’t fully explored or predictable. Applicant acknowledges (p. 12 ¶2) the He reference teaches YAP might be a potent therapeutic target to regulate angiogenesis but argues He isn’t completely definitive because the Hippo pathway controls angiogenesis independent of YAP. Applicant argues (p. 12 ¶3) that the justification underlying the obviousness rejection is an oversimplification. Applicant argues (p. 13 ¶1-2) some of the references discuss the Hippo pathway in cell types besides for skeletal muscle.
Regarding Applicant’s arguments about the effects of modulating the Hippo pathway being uncertain in skeletal muscle, it is in part because the role of SAV1 upstream of YAP is known in other cell types that an artisan would’ve been motivated to try inhibiting SAV1 in skeletal muscle, precisely to determine whether it functions similarly. Just because an outcome isn’t 100% predictable doesn’t mean it isn’t obvious to try doing the experiment, especially when SAV1-inhibiting siRNA are readily available. “A reasonable expectation of success” isn’t a requirement for a guaranteed outcome.
Applicant’s arguments aren’t persuasive because the references as a whole indicate that SAV1 is upstream of YAP. The references provide a basis for an “obvious to try” rationale:
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): Watt 2015 teaches (§Main text ¶1) the Hippo pathway suppresses YAP activity by post-translational regulation and nuclear exclusion and they show (§Results, see subheadings within Results) YAP is required to maintain basal skeletal myofiber size, YAP promotes hypertrophy, and YAP is upregulated to mitigate muscle atrophy. Still, Watt describes (§Main text ¶1) the role of each element of the Hippo pathway in skeletal muscle is not completely understood. That indicates there was a recognized need in the art to determine the role of each element of the Hippo pathway (including SAV1) in regulation of adult skeletal muscle fibers.
Regarding (2): The art teaches (Watt 2015 and Watt) the Hippo pathway has known involvement in skeletal muscle regeneration because (§Yap and Taz promote muscle growth via Tead in Post-natal muscle fibers) activating YAP in post-natal muscle fiber increases cell size and promotes muscle mass, and (same §) inhibiting YAP with shRNA reduces muscle mass, protein synthesis, and myofiber cross sectional area. Furthermore, the art teaches (Plouffe, He, Watt) SAV1 is a known negative regulator of YAP which is upstream of YAP. The art teaches (WO074 ¶23-25, ¶116-123) inhibiting SAV1 in heart improves cardiac muscle regeneration and (WO117 p. 34 ¶2) expression of angiopoietins. Therefore, an artisan would have wanted to know whether inhibiting SAV1 would have had the same positive effects on regenerating muscle fibers and inducing angiogenesis in a second muscle type, namely skeletal muscle. An artisan would have wanted to know whether inhibiting SAV1 (a negative regulator of YAP) would have the same effects on skeletal muscle as (Watt 2015 § YAP promotes hypertrophy via TEAD transcription factors) overexpressing YAP. There would have been a finite number of potential solutions: inhibiting SAV1 to determine whether doing so increases (1) YAP expression and (2) regeneration and angiogenesis in any muscle, including skeletal muscle.
Regarding (3): It would have been a simple matter to use known SEQ ID NOs, described in the art to accomplish an outcome in one muscle type (i.e., cardiac muscle), to obtain the same or similar outcomes in a different muscle type (i.e., skeletal muscle).
Therefore the 103 rejection is based in part on a reasonable “obvious to try” rationale.
Applicant argues (p. 14 ¶1, p. 15 ¶3-4) the Watt references focus on YAP, not SAV1. Applicant discusses that Watt teaches that experiments inhibiting YAP resulted in different outcomes: shRNA inhibition reduced muscle mass etc. but a CRE-recombinase experiment showed no differences in muscle fiber size. That argument isn’t persuasive because (1) those experiments examined two different things: the shRNA experiment tested the effect of YAP-targeting shRNA in adult mice (and found reduced muscle mass etc.) whereas the CRE-recombinase experiment looked at the effects of Yap knockout from embryonic stages. Watt notes this and reiterates the importance of YAP expression in adult muscle:
The reason for the different results of these studies remains to be determined but may be due to the timing/developmental stage of the YAP knockdown/knockout (i.e. embryonic muscle vs mature adult muscle), or to changes in food intake and activity in the tissue specific knockout model that would not influence the findings when comparing to a contralateral muscle within the same animal. Despite this, mice lacking skeletal muscle expression of Yap display reduced force generating capacity, due to alterations in the formation and regeneration of the neuromuscular junction, suggesting distinct consequences may occur upon loss of Yap in skeletal muscle depending on the development stage assessed (42).
Furthermore, (2) those apparently disparate outcomes would have motivated further investigation to experiment further and (3) overexpressing YAP promoted hypertrophy in skeletal muscle and SAV1 is (and was known before the effective filing date of the claimed invention) a known negative regulator of YAP. Those findings justify a finding of obviousness under “obvious to try”.
Applicant’s argues (pp. 14-15 ¶2-4) that the Office Action overstates Watt’s teachings about skeletal muscle regeneration because the art doesn’t explicitly teach inhibiting SAV1 in a therapeutic context. Applicant argues (same §) that promoting skeletal muscle hypertrophy isn’t the same as regenerating damaged skeletal muscle. Applicant concedes (p. 15 ¶3) that Watts teaches transient YAP activation may enhance satellite cell proliferation but argues that the results wouldn’t have been a predictable therapeutic strategy. Those arguments aren’t persuasive because Applicant doesn’t provide any evidence why it is not obvious to try using the same mechanism that has been demonstrated to successfully promote skeletal muscle hypertrophy (i.e., increasing YAP expression) to regenerate skeletal muscle. Regarding the arguments about transient YAP activation, a person of ordinary skill knows that one benefit of inhibitory nucleic acids is that their effects are transient.
ATTORNEY ARGUMENTS CANNOT TAKE THE PLACE OF EVIDENCE
The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
See MPEP § 2145 generally for case law pertinent to the consideration of applicant’s rebuttal arguments.
MPEP §716.01(c)
Applicant argues (p. 16 ¶1-2, pp. 17-18 ¶2-1) the cited references indicate outcomes of inhibiting the Hippo pathway would have been unpredictable and inhibiting SAV1 does not provide a reasonable expectation of success in attaining the claimed outcomes.
Regarding Applicant’s arguments, as discussed, the art teaches that SAV1 is upstream of and negatively regulates YAP. The art teaches that SAV1 causes YAP phosphorylation which keeps it out of the nucleus and that nuclear YAP is necessary for its downstream functions. The art (Plouffe) teaches SAV1 deficient cells re-enter the cell cycle and undergo cell division and SAV1 hearts have improved recovery after ischemia, indicating SAV1 deficiency imparts increase regenerative potential in heart. The art (Watt) teaches that using shRNA to inhibit YAP in adult mice reduces skeletal muscle mass and fiber size and (Watt 2015) overexpressing YAP produces skeletal muscle hypertrophy. The art (He) teaches that YAP deficiency generally suppresses angiogenesis from endothelial cells. Furthermore, the cited art WO117 teaches (p. 34 ¶2) 6 weeks after myocardial infarction, SAV1-KO hearts revealed increased vasculogenesis genes encoding angiopoietins, fibroblast growth factors, and vascular endothelial growth factors. The art (WO074 ¶7, ¶16, ¶45) teaches using the same sequences as those claimed to treat any medical condition that directly or indirectly affects cardiac muscle cells and to regenerate heart cells, and inhibiting HIPPO to restore regenerative capacity in heart tissue. Although some of the results discussed (i.e., experiments wherein SAV1 was inhibited) were in heart and not in skeletal muscle, they still indicate that inhibiting SAV1 increases cellular regeneration and growth factor proteins involved in blood vessel growth. The results wherein YAP was inhibited demonstrate a role for the Hippo pathway in skeletal muscle specifically. Applicant discusses that outcomes of inhibiting Hippo pathway in cell types besides heart are unpredictable, but presents no evidence why that is the case. Applicant provides no evidence explaining why skeletal muscle wouldn’t be expected to respond to SAV1 inhibition the same way that heart muscle does.
Regarding Applicant’s argument (pp. 13-14 ¶4) that Watt states that the Hippo pathway is understood in mitotically active tissues including developing heart but not understood in adult skeletal muscle fibers, that isn’t persuasive because WO117 teaches (p. 33 §Example 1, ¶151-155) their experiment (wherein they observed inhibiting SAV1 increased expression of genes encoding angiopoietins) used adult mice. As described above, that experiment and other findings provide evidence it would have been obvious to try inhibiting SAV1 to increase YAP and to obtain similar outcomes as those produced by overexpressing YAP.
Regarding Applicant’s arguments (pp. 16-17 ¶2-3), here Applicant argues that WO074’s ¶51 is about individuals who suffer from degeneration of skeletal muscle fibers as a result of their cardiac condition and that the ¶ does not disclose that degeneration of skeletal muscles itself is treated by the WO074 methods. That isn’t persuasive because WO074 (§Abstract) is broadly directed to:
…methods and compositions that provide therapy for at least one medical condition that directly or indirectly affects cardiac muscle cells… the medical condition may be of any kind, including a cardiac condition… The medical condition may have a cardiac condition as its primary symptom or cause or it may be a secondary symptom or cause… [emphasis added.]
That indicates the invention of WO074 can be used (their words) to treat any medical condition. WO074 teaches (¶16) the method of treating is for individuals in need of cardiomyocyte renewal and (¶9, ¶18) the conditions can be treated by providing the exact sequences instantly claimed. WO074 teaches (¶45) the Hippo signaling pathway represses cardiac regeneration. Regarding Applicant’s arguments about ¶51, those aren’t persuasive for several reasons. As stated, the Abstract teaches the methods and compositions are for treating any medical condition that directly or indirectly affects cardiac cells, and the medical condition can be any kind of medical condition. That statement is in conflict with Applicant’s interpretation of WO074 that requires a cardiac condition. Also, ¶50-51 describe various embodiments of their invention; those don’t conflict with the Abstract that teaches treating any medical condition. In addition, WO074 is broadly directed to (§Abstract, ¶3) treating DMD which affects all muscle. Furthermore, nothing in the claims requires any specific source of the skeletal atrophy, injury, or sarcopenia. WO074 describes that (¶51) cardiac conditions can result in degeneration of skeletal muscle fibers, and it would have been obvious to use the compounds disclosed in WO074 to treat any aspect of cardiac conditions, especially those disclosed by the reference itself.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., degeneration of skeletal muscle caused by something other than a cardiac condition) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Altogether, the preponderance of the evidence weighs in favor of an obvious to try rationale for inhibiting SAV1 to regenerate myofibers, induce proliferation of cells in muscle tissue (including satellite cells), treat limb ischemia in a limb (by increasing angiogenesis and, therefore, blood flow), and increase angiogenesis in any tissue, including skeletal muscle. As discussed, the art teaches using the same sequences to regenerate cardiac muscle. As stated, there is no evidence that skeletal will behave differently from cardiac muscle.
Finally, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The obviousness rejection is based on the synthesis of the cited art. The rejection explains that the art teaches that the Hippo pathway in general and YAP specifically have known roles in skeletal muscle regeneration. The rejection explains that the art teaches that SAV1 negatively regulates YAP and that (He, WO117) inhibiting SAV1 induces angiogenesis in tissues besides for skeletal muscle. Applicant asserts that the Hippo signaling pathway is unpredictable but hasn’t explained why skeletal muscle would be expected to responds differently than cardiac muscle. The statute requires a reasonable expectation—not a 100% guarantee—of success, and the preponderance of the evidence weighs in favor of that.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
As discussed, the art teaches that the Hippo pathway in general and YAP specifically have known roles in skeletal muscle regeneration. The rejection explains that the art teaches that SAV1 negatively regulates YAP and that inhibiting SAV1 induces angiogenesis in tissues besides for skeletal muscle. Those facts indicate that it would have been obvious to try using sequences described to be beneficial for obtaining an outcome in one muscle type (i.e., cardiac muscle) to obtain that same outcome in a second muscle type (i.e., skeletal muscle). The 103 rejections are maintained for those reasons.
In the interest of compact prosecution, it is noted that Figs. 6-8 and 10-13 show quantitative outcomes of using the claimed methods. Applicant is recommended to include, as appropriate, some of those functional outcomes in Claims 1-4.
NDSP
The arguments against the NSDP rejections (pp. 18-19) are not persuasive for the same reasons the arguments against the 103 rejections are not persuasive.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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
