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 .
Applicant's amendments to the claims and arguments filed on 09-26-2025 have been received and entered. Claims 1, 3, 7, 8, 15, 16, have been emended. Claims 2, 13-14, 20-23 have been canceled. Claims 1, 3-12, 15-19, 24-25 are pending in the instant application.
Election/Restrictions
Applicant's election with traverse of Group I (claims 1, 7-12, 23-24) in the reply filed on 01-29-2025 is acknowledged. The traversal is on the ground(s) that claims 1, 3, and 15 have been amended from reciting sterol biosynthesis to reciting mevalonate biosynthesis and Keating is silent on the benefit of the activation of mevalonate pathway for the treatment or prevention of cardiac disease or a cardiac disorder. This is not found persuasive because according to the specification of the claimed invention "mevalonate pathway" or "mevalonate biosynthesis" is used to refer to that portion of the sterol biosynthetic pathway that converts acetyl-CoA to isopentenyl pyrophosphate (see the specification page 14, lines 25-27). Also, the instant disclosure provides an agent that activates or upregulates sterol biosynthesis in a cardiomyocyte, such as mevalonate biosynthesis and/or isoprenoid biosynthesis (see the specification page 27, lines 19-21). The agent which upregulates or activates sterol biosynthesis, inclusive of the mevalonate pathway and the isoprenoid pathway can be or comprises a p38a inhibitor (see the specification page 20, lines 6-12). Thus, agent such as p38a inhibitor that activates or upregulates sterol biosynthesis can also activate or upregulates mevalonate biosynthesis. Further, the instant disclosure also teaches that a p38a inhibitor can be SB203580 (see the specification page 20, lines 27-29). Since Keating teaches p38 inhibitors can be used to increase proliferation and/or de-differentiation of postmitotic mammalian cardiomyocytes, and SB203580 is a highly potent pyridinyl imidazole inhibitor of p38 ([0029], page 3), the teachings of Keating satisfy the claims. However, Upon further consideration, Group II (claims 3-6) is hereby rejoined with of Group I (claims 1, 7-12, 23-24) .
The requirement is still deemed proper and is therefore made FINAL.
Claims 15-19, 25 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 01-29-2025.
Claims 1, 3-12, 24 are under consideration.
Priority
This application is a 371 of PCT/AU2019/050238 filed on 03/18/2019. It is noted that there is no foreign priority claim.
Withdrwan-Claim Rejections - 35 USC § 112
Claims 8-9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. In view of Applicants' amendment to claim 8, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
Maintained in modified form - Claim Rejections - 35 USC § 103 - necessitated by amendments
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.
Claim 1, 3-12, 24 are rejected under 35 U.S.C. 103 as being unpatentable over Mohamed et al (Pub .No.: US 2018 /0112282 A1, Pub. Date: Apr. 26 , 2018) as evidenced by Mather et al (The International Journal of Biochemistry & Cell Biology 41 (2009) 561–569, doi:10.1016/j.biocel.2008.07.007).
Claim interpretation:
The specification of the claimed invention teaches that the term "mevalonate pathway" or "mevalonate biosynthesis" is used herein to refer to that portion of the sterol biosynthetic pathway that converts acetyl-CoA to isopentenyl pyrophosphate (Page 14, lines 25-27). Thus, mevalonate biosynthesis is interpreted as portion of the sterol biosynthetic pathway that must also be able to converts acetyl-CoA to isopentenyl pyrophosphate.
The specification of the claimed invention teaches that an agent which upregulates or activates sterol biosynthesis, inclusive of the mevalonate pathway and the isoprenoid pathway, such as an enzyme thereof, modulates a signaling effector upstream or downstream of the sterol biosynthesis pathway. In particular embodiments, the signaling effector is selected from the group consisting of p38α, MST1, a TGF-beta receptor, a BMP receptor and any combination thereof. To this end, the agent can be or comprises a p38a inhibitor, a MST1 inhibitor, a TGF-beta receptor inhibitor and/or a BMP receptor inhibitor (Page 20, lines 6-12) . Thus, a p38a inhibitor, a MST1 inhibitor, a TGF-beta receptor inhibitor and/or a BMP receptor inhibitor are interpreted as an agent which upregulates or activates sterol biosynthesis, inclusive of the mevalonate pathway and the isoprenoid pathway.
The specification of the claimed invention teaches that it is contemplated herein that an inhibitor of the TGF-β signaling pathway can be, for example, a TGF-β receptor inhibitor (e.g., a small molecule, an antibody, an siRNA), a TGF-β sequestrant (e.g., an antibody, a binding protein), an inhibitor of receptor phosphorylation, an inhibitor of a SMAD protein, or a combination of such agents (Bridging last paragraph on page 21 to 22). Thus, a TGF-β receptor inhibitor is interpreted as a small molecule, an antibody, an siRNA, a TGF-β sequestrant (e.g., an antibody, a binding protein), an inhibitor of receptor phosphorylation, an inhibitor of a SMAD protein, or a combination of such agents.
Regarding to claim 1, 3 and 12, Mohamed et al provide methods of inducing proliferation and/or cell cycle reentry of a postmitotic cell, the methods comprising contacting the postmitotic cell with an effective amount of a composition in an amount effective to stimulate proliferation and/ or cell cycle reentry of the postmitotic cell ([0072], page 6). The postmitotic cell is selected from the group consisting of a cardiomyocyte etc. ([0011], page 1). The term " effective amount" refers to an amount that is sufficient to induce proliferation and/or cell cycle reentry of cardiac cells ( e.g., cardiomyocytes) ([0051], page 4). In some embodiments, the postmitotic cell is contacted with a transforming growth factor β inhibitor, A transforming growth factor beta ( TGF-β) inhibitor is a compound that inhibits TGF-β signal transduction by inhibiting any of the factors constituting the TGF-β signal transduction system pathway, such as TGF-β ligand, TGF-β Type I receptors, TGF-β Type II receptors, TGF-β Type III receptors (β -glycan and endoglin ), soluble forms of the TGF-β receptors, Smad proteins, antibodies against receptors and ligands implicated in the signaling pathway , nucleic acid based molecules ( e.g., antisense, siRNA, aptamers and ribozymes) targeting the pathway members, or a combination thereof ([0102], page 8).
Mohamed et al also provide cells and compositions for treating diseases, such as cardiovascular diseases (Abstract) (For claim 3, the claimed: thereby treat or repair the cardiac damage in the subject).
Since Mohamed et al teach contacting the cardiomyocytes with the same agents (e.g., a transforming growth factor β receptor inhibitor ) as same as the claimed invention for inducing cardiomyocyte proliferation, a person of ordinary skill in the art would recognize that the same agent would have the same characteristics, activities and effects. The same agent would have pro-proliferative effects in cardiomyocytes, does not induce the proliferation in fibroblasts and does not decrease force or increase relaxation time in an immature human cardiac organoid (hCO), as evidenced by applicant own disclosure (Page 20, lines 6-12, and see claim 7 of the claimed invention) (For claim 1 and 3, the claimed: “wherein the agent has pro-proliferative effects in cardiomyocytes, does not induce the proliferation in fibroblasts and does not decrease force or increase relaxation time in an immature human cardiac organoid (hCO)”).
Additionally, since Mohamed et al teachings encompass contacting the cardiomyocytes with any transforming growth factor β receptor inhibitor as same as the claimed invention for inducing cardiomyocyte proliferation, these transforming growth factor β receptor inhibitor agents should be able to maintains, at least in part, contractile function of proliferated cardiomyocytes as evidenced by applicant own disclosure (see instant specification page 26, lines 22-25). Specifically, instant specification also teaches that “our screen identified compounds that induced proliferation without affecting contractile parameters (Figure 2G,H). These compounds included inhibitors of three distinct pathways including p38α/β, P2RX7, and TGFβR/BMPR” (see page 41, lines 27-30). (For claim 12, the claimed: “the agent maintains, at least in part, contractile function of proliferated cardiomyocytes”).
Further, activating mevalonate biosynthesis in cardiomyocyte by agent such as TGF- β inhibitor can be evidenced by Mather et al who teach that excessive production of TGFβ and phosphorylation of p38 occur as a consequence of inhibition of the mevalonate pathway (Page 567, right column, 3rd para) and also teach the link between the mevalonate pathway and TGF β1 secretion and action: Ras is known to induce the phosphorylation of MAPK sites on Smad2 and Smad3, inhibiting their ability to mediate TGF-β anti-proliferative responses (Page 568, right column, 2nd para) (Note: The prenylation of Ras proteins is critically dependent on the formation of the isoprenoid metabolites ( building blocks of mevalonate pathway) (see page 562, left column, 1st para.)). Thus, inhibiting TGF-β anti-proliferative responses would activate mevalonate pathway.
Also, Mohamed et al teach embodiment using a transforming growth factor β inhibitor ([0102], page 8), and embodiment using p38 inhibitor, a p21 inhibitor, a p57 inhibitor, or a pharmaceutically acceptable derivative thereof can be used to facilitate an increase in proliferation and /or cell cycle reentry ([0179], page 16). Thus, a person of ordinary skill in the art before the effective filing date of the rejected claims would have options to use a transforming growth factor β inhibitor without using a p38a inhibitor. (For claim 1, the claimed: the agent is not a p38a inhibitor.)
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Mohamed et al for inducing proliferation of cardiomyocyte as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Mohamed et al stated that “It is contemplated that addition of a TGF-β inhibitor to the composition acts to improve cell survival” ([0103], page 8), and “these in vivo data demonstrated that adult cardiomyocytes induced to proliferate and/ or reenter the cell cycle can improve cardiac function and structure after myocardial infarction” ([0289], page 22) and “it would be beneficial to provide methods for reinitiating postmitotic cell division to regenerate cells and/or replace damaged cells” ([0004], page 1). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Mohamed et al were successful in inducing cardiomyocytes to proliferate, with working examples and data.
Regarding to claim 4 and claim 7, Mohamed et al teach that this disclosure is predicated on the discovery that certain agents can induce proliferation and /or cell cycle reentry of postmitotic cells and is directed , in part, to methods of inducing proliferation and/or cell cycle reentry of a postmitotic cell ([0005], page 1), the postmitotic cell is a cardiomyocyte etc. ([0011], page 1), the postmitotic cell is contacted with an effective amount of a CDK activator, a transforming growth factor β inhibitor, or combinations thereof. A transforming growth factor beta ( TGF- β) inhibitor is a compound that inhibits TGF- β ligand, TGF- β Type I receptors, TGF- β Type II receptors, TGF- β Type III receptors (β -glycan and endoglin ), soluble forms of the TGF- β receptors ([0102], page 8). Mohamed et al alsoteach induction of proliferation in postmitotic human cardiomyocytes in example 2 with addition of TGF-βi ([0290], page 22)
Regarding to claim 5, Mohamed et al teach the methods include, but are not limited to , individuals having a congenital heart defect, individuals suffering from a condition that results in ischemic heart tissue ( e .g ., individuals with coronary artery disease), and the like ([0201], page 18)
Regarding to claim 6, Mohamed et al teach that the composition can be administered to a subject in need thereof by any mechanisms commonly known to those of skill in the art. Non -limiting examples include oral, systemic (e.g., transdermal, intranasal or by suppository ), or parenteral (e .g., intramuscular, intravenous or subcutaneous) administration ([0114], page 9).
Regarding to claim 8-9, as described above, contacting/treating one or a plurality of cardiomyocytes with the same agents (e.g., TGF-β inhibitor or p38 inhibitor) as the claimed invention for inducing cardiomyocyte proliferation was taught by Mohamed et al. Thus, it would be expected that the treated cardiomyocytes would be structurally and functionally similar to one claimed in the instant application such as activating mevalonate pathway that lead to increase the expression and/or activity of one or more proteins associated mevalonate biosynthesis. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430,433 (CCPA 1977). Additionally, Since Mather et al teaches high glucose exposure to human endothelial cells increased secretion of transforming growth factor β1 (TGFβ1) and drugs known to inhibit 3-hydroxy-3 methyl coenzyme A (HMG-CoA) reductase results in an identical pattern of altered cell growth and cytokine secretion (Page 561, left to right column). Therefore, inhibition of secretion of TGFβ1 would reasonably lead to increased HMG-CoA reductase. In view of forgoing, absent evidence to contrary and/or any unexpected result, it is reasonable to expect that cardiomyocytes treated with the same agents as the claimed invention would have similar effects/properties such as increasing the expression of proteins associated mevalonate biosynthesis.
Regarding to claim 10-11, Mohamed et al teach the composition comprises a chemical that increases expression of endogenous CCND1 ([0115], page 10).
Regarding to claim 24, Mohamed et al teach in some embodiments , the contacting is conducted in vitro or in vivo ([0010], page 1).
Response to Arguments
Applicant's arguments filed 09-26-2025 have been fully considered but they are not persuasive.
Applicants argue that claims 1 and 3 have been amended to further define that the agent used for inducing cardiomyocyte proliferation does not decrease force or increase relaxation time in human cardiac organoids (hCOs). Applicant submits that this functional limitation is not taught or suggested by the cited prior art.
While Mohamed discusses cardiomyocytes, the disclosure is broad and directed to postmitotic cells generally. The reference is silent on any agent that achieves the specific functional outcomes presently claimed, particularly with respect to maintaining cardiac contractility and rhythm. It is well-established that approximately 90% of drug candidates fail to progress from Phase I trials to clinical approval, largely due to lack of efficacy in human models. This issue is especially pronounced in cardiovascular research, where drug development lags behind other fields despite cardiovascular disease remaining the leading global cause of death.
To address this translational gap, the present inventors developed a rigorous drug screening pipeline to identify pro-regenerative small molecules with minimal adverse effects on cardiac function. This pipeline includes: Screening a 5,000-compound library for pro-proliferative activity in iPSC-derived cardiomyocytes using EdU. Eliminating compounds that also induce proliferation in fibroblasts. Screening remaining hits in immature hCOs using Ki-67. Excluding compounds that decrease force or increase relaxation time. (Remarks, page 6)
Response to Arguments:
The base claim 1 and 3 now require a very specific combination of functionalities while claiming an agent very generically with regard to structure : the agent has pro-proliferative effects in cardiomyocytes, does not induce the proliferation in fibroblasts and does not decrease force or increase relaxation time in an immature human cardiac organoid (hCO). While the amended limitations further limit the scope of the claims 1 and 3, these limitations still encompass agents such as transforming growth factor (TGF)-beta receptor inhibitors. The instant claim 7 and specification of the claimed invention teaches that the agent can be or comprises a TGF-beta receptor inhibitor (see the specification Page 20, lines 6-12). The specification of the claimed invention teaches that “it is contemplated herein that an inhibitor of the TGF-β signaling pathway can be, for example, a TGF-β receptor inhibitor (e.g., a small molecule, an antibody, an siRNA), a TGF-β sequestrant (e.g., an antibody, a binding protein), an inhibitor of receptor phosphorylation, an inhibitor of a SMAD protein, or a combination of such agents” (see the specification, Bridging last paragraph on page 21 to 22). Since the teachings of Mohamed et al encompass any transforming growth factor β inhibitor, such as agents that inhibits TGF-β Type I receptors, TGF-β Type II receptors, TGF-β Type III receptors etc. ([0102], page 8), the teachings of Mohamed et al also encompass the scope of the agents recited in the claims.
The specification of the claimed invention also teaches that “it has been recently demonstrated that the TGFβR inhibitor, SB431542, synergizes with cyclin-dependent kinases to induce adult rodent cardiomyocyte proliferation in vivo” (see the specification, page 43, lines 2-4). Additionally, Mohamed et al teach that Cells were treated with the cyclin dependent kinase (CDK ) such as CDK1AF, CDK4 in combinations of TGF-βi (SB431542) ([0290], page 22), and the combination of cyclin dependent kinase and TGF-β inhibitor SB431542 resulted in best survival and increase in proliferative postmitotic cardiomyocytes ([0291], page 22). Thus, a person of ordinary skill in the art before the effective filing date would be motivated to apply teachings of Mohamed et al and arrive at the claimed invention.
2. Applicants argue that the cited prior art does not disclose or suggest this multi-tiered screening strategy, nor does it teach the importance of preserving cardiac contractile function during proliferation induction (remarks, page 7).
Response to Arguments:
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., “multi-tiered screening strategy”; “the importance of preserving cardiac contractile function during proliferation induction.”) 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).
3. Applicants argue that Mohamed et al teach SB431542 alone was insufficient for robust activity, and the optimal cocktail included CDKIAF, CDK4, CCNB1, and CCND1 (see, e.g., paragraph [0291 ]). Thus, the combination of Mohamed and Mather does not teach or suggest the claimed invention, which identifies agents with distinct functional profiles and mechanisms of action (remarks, page 7).
Response to Arguments:
It is noted that, similar to the claimed invention, Mohamed et al encompass any transforming growth factor β inhibitor, such as agents that inhibits TGF-β Type I receptors, TGF-β Type II receptors, TGF-β Type III receptors etc. ([0102], page 8). Further, the claims do not prevent to use transforming growth factor β inhibitor in combination with other factors. Further, the claims do not require “robust activity” but only require “activating mevalonate biosynthesis”.
4. Regarding to applicants’ arguments for the Mills et al references for claim 12 in the remarks, page 7, the 35 USC § 103 rejections necessitated by amendments have been modified and rewritten as described above. Additionally, as per MPEP 2112(II) inherent feature need not be recognized at the relevant time: There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).
New-Claim Rejections - 35 USC § 112-- necessitated by amendments
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, 3-12, 24 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.
Claims are directed to a method of inducing cardiomyocyte proliferation including contacting one or a plurality of cardiomyocytes with an effective amount of any agent capable of at least partly activating mevalonate biosynthesis wherein the agent has pro-proliferative effects in cardiomyocytes, does not induce the proliferation in fibroblasts and does not decrease force or increase relaxation time in an immature human cardiac organoid (hCO). The agent is or comprises any p38a inhibitor, any mammalian STE20-like kinase 1 (MST1) inhibitor, any transforming growth factor (TGFl-beta receptor inhibitor and/or any bone morphogenic protein (BMP) receptor inhibitor.
In analyzing whether the written description requirement is met for the genus claim, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics, specific features and functional attributes that would distinguish different members of the claimed genus. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B. V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaffv. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304,312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43). USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991).
The claims encompass a genus of any agent is or comprises any p38a inhibitor, any mammalian STE20-like kinase 1 (MST1) inhibitor, any transforming growth factor (TGF)-beta receptor inhibitor and/or any bone morphogenic protein (BMP) receptor inhibitor.
The instant specification teaches “The compound library included -5,000 biologically annotated pre-clinical, clinical, and tool compounds. They were selected based on a combination of criteria including balancing the number of external/internal compounds, diversity of annotated targets to cover greater than 1500 biological targets, and known targets associated with cell proliferation ……. Subsequently, 105 potential hit compounds were screened over a 3 log-scale concentration range (0.1, 1, and 10 µM, ~ 1,000 hCO) in immature hCOs, which have a robust proliferative response to mitogenic stimuli (Mills et al., 2017a; Voges et al., 2017) (Figure 2A) ……. Screening identified several small molecular weight molecules that were capable of inducing proliferation (Figure 2D) and the top 9 hits in the hCO also induced >50% increase in proliferation in the 2D assay (Table 1). Intriguingly, many compounds that induced proliferation in 20 failed to induce proliferation even in the immature hCOs (Figure 2F,Table 1)” (Bridging last para of Page 40-41).
The instant specification teaches “Of the compounds that induced proliferation in the immature hCO, many decreased force of contraction (Figure 2E,G). Of the 8 compounds that activated proliferation and reduced force to less than 10%, 5 of them inhibited GSK3 (green triangles) and 2 of them activated adenosine receptor 2A (purple triangles). Additionally, other pro-proliferative compounds (compounds 8 and 51) prolonged the 50% relaxation time (Figure 2H), which is indicative of an increased risk of arrhythmogenesis (Mills et al., 2017a)” (see page 41, lines 17-23), and “our screen identified compounds that induced proliferation without affecting contractile parameters (Figure 2G,H). These compounds included inhibitors of three distinct pathways including p38α/β, P2RX7, and TGFβR/BMPR (compounds 3, 63 and 65, respectively)” (see page 41, lines 27-30).
Thus, applicant own disclosure provide evidence that not all compounds (any p38a inhibitor, any mammalian STE20-like kinase 1 (MST1) inhibitor, any transforming growth factor (TGF)-beta receptor inhibitor and/or any bone morphogenic protein (BMP) receptor inhibitor) can be correlated with the functionalities of “pro-proliferative effects in cardiomyocytes, does not induce the proliferation in fibroblasts and does not decrease force or increase relaxation time in an immature human cardiac organoid (hCO)”.
The specification of the claimed invention teaches that it is contemplated herein that an inhibitor of the TGF-β signaling pathway can be, for example, a TGF-β receptor inhibitor (e.g., a small molecule, an antibody, an siRNA), a TGF-β sequestrant (e.g., an antibody, a binding protein), an inhibitor of receptor phosphorylation, an inhibitor of a SMAD protein, or a combination of such agents (Bridging last paragraph on page 21 to 22). However, there is no evidence on the record that any TGF-β receptor inhibitors as described by the instant specification have known structural relationships to each other and would have similar functionalities of “pro-proliferative effects in cardiomyocytes, does not induce the proliferation in fibroblasts and does not decrease force or increase relaxation time in an immature human cardiac organoid (hCO)”.
The specification of the claimed invention teaches that “The MST1 inhibitor may be any type of compound. For example, the compound may be a small organic molecule or a biological compound such as an antibody or an enzyme. To this end, a person skilled in the art may be able to determine whether a compound is capable of inhibiting MST1 activity and/or expression by any means known in the art.” (Page 21, lines 6-9). However, there is no evidence on the record that any type of compound such as an antibody or an enzyme would function as MST1 inhibitor let alone have similar functionalities of “pro-proliferative effects in cardiomyocytes, does not induce the proliferation in fibroblasts and does not decrease force or increase relaxation time in an immature human cardiac organoid (hCO)”.
The specification of the claimed invention teaches that an inhibitor of the BMP signaling pathway can be, for example, a BMP receptor inhibitor (e.g., a small molecule, such as LDN- 193189, an antibody, an siRNA), a BMP sequestrant (e.g., an antibody, a binding protein), an inhibitor of BMP receptor phosphorylation, an inhibitor of a SMAD protein, or a combination of such agents (Page 22, lines 14-18). However, there is no correlation structurally and functionally between these molecules that would have similar functionalities of “pro-proliferative effects in cardiomyocytes, does not induce the proliferation in fibroblasts and does not decrease force or increase relaxation time in an immature human cardiac organoid (hCO)”.
The claimed invention as a whole is not adequately described if any p38a inhibitor, any mammalian STE20-like kinase 1 (MST1) inhibitor, any transforming growth factor (TGF)-beta receptor inhibitor and/or any bone morphogenic protein (BMP) receptor inhibitor can be used as intended to have similar functionalities which are not adequately described in the specification and not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 UsPQ2d 1641, 1646 (1998).
The specification lacks sufficient variety of species to reflect this variance in the genus showing contemplated functionalities of “pro-proliferative effects in cardiomyocytes, does not induce the proliferation in fibroblasts and does not decrease force or increase relaxation time in an immature human cardiac organoid (hCO)”. The specification does not provide sufficient descriptive support for the myriad of variant embraced by the claims.
Overall, what these statements indicate is that the Applicant must provide adequate description of such core structure and functions related to that core structure such that the Artisan of skill could determine the desired effect. Hence, the analysis above demonstrates that Applicant has not determined the core structure for full scope of the claimed genus for contemplated any compounds (any p38a inhibitor, any mammalian STE20-like kinase 1 (MST1) inhibitor, any transforming growth factor (TGF)-beta receptor inhibitor and/or any bone morphogenic protein (BMP) receptor inhibitor).
The skilled artisan cannot envision the detailed chemical structure of the encompassed any any compounds other than those described in the specification, and therefore conception is not achieved until reduction to practice has occurred. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v.Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632