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 .
Status of the Claims
The preliminary amendment filed 12/05/2022 is acknowledged. No restriction is being imposed in this case. Claims 7-9, 14 and 16 are amended. Claims 1-17 are under examination.
Drawings
The drawings are objected to because they are blurry, making them difficult to read and interpret. Most of the labels are blurry and the x-axis label is not legible in Figure 1A, for example. In addition, there are two copies of SUPP Figure 2A. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See p. 17, lines 15-17 of the instant specification. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Effective Filing Date
Applicant’s claim for the domestic benefit of prior-filed applications under 35 U.S.C. 119(e) and 365(c) is acknowledged. No foreign priority claims are made. Under the AIA , the effective filing date of a claimed invention is the earlier of:
The actual filing date of the application;
OR
The filing date to which the application is entitled to a right of foreign priority or domestic benefit as to such claimed invention.
Note that with regard to claiming domestic benefit of prior-filed applications, MPEP 211.05 sets forth the disclosure requirements:
To be entitled to the benefit of the filing date of an earlier-filed application, the later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or earlier-filed nonprovisional application or provisional application for which benefit is claimed); the disclosure of the invention in the prior application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, except for the best mode requirement. See Transco Prods., Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994). Accordingly, the disclosure of the prior-filed application must provide adequate support and enablement for the claimed subject matter of the later-filed application in compliance with the requirements of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, except for the best mode requirement.
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Based on the information given by Applicant and an inspection of the prior applications, the examiner has concluded that the subject matter defined in the instant claims 1-6 and 8-13 is supported by the disclosure in PCT/US2021/036023 and provisional application serial no. 63/035,538. The subject matter in claims 7 and 14-17 is not supported by the ‘538 provisional, however, because it does not disclose all of the agents recited in claims 7 and 14-17. Thus, the effective filing date of claims 1-6 and 8-13 is 06/05/2020 and claims 7 and 14-17 is 06/04/2021.
Claim Objections
Claims 2-9, 14 and 16 objected to because of the following informalities.
(i) Claims 2-6 recite “an agent that modulate”, however, presumably “an agent that modulates” was intended.
(ii) Claims 7-9, 14 and 16 recites “any one of claims 1”, however, “claim 1” will suffice since the claims are no longer multiply dependent.
(iii) Claim 9 has a period after the word “neurodegeneration” in line 3 and appears to be made up of two sentences.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-6, 10-12, 16 and 17 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.
(i) Claim 2-6 and 16 recite the receptor “ACVR1” followed by “activin” in parentheses. In this case, the parenthetical is exemplary because activin is not the only ACVR1 ligand, but rather, appears to be a preferred ligand. Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. In the instant case, it is unclear whether the parenthetical “activin” is intended to be a limitation or a preference. For example, one skilled in the art could not be certain that a administering a BMP inhibitor that modulates an ACVR1 ligand other than activin would infringe upon the claim. Note this is different than the parenthetical recitation of “(Alk2)” in claims 2-6 and 7 because “Alk2” is an alternative term for “ACRV1”. Claims 10 and 12 recite “e.g.” parenthetically, which means “for example”, followed by a list of embodiments. The phrases “e.g.” or “for example” render the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. Finally, the phrase “In one embodiment” in claim 9, followed by a list of diseases/conditions, also reads like exemplary language. See MPEP § 2173.05(d).
(ii) Claim 7 recites the limitation “wherein the inhibitor is of ACVR1 (Alk2) is LDN-212864, dorsomorphin…” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim since claim 1, from which claim 7 depends, does not specify the BMP receptor is ACVR1. The language makes it unclear as to whether claim 7 is intending to further define the BMP receptor. The claim could be amended to recite something like “wherein the BMP receptor inhibitor is an inhibitor of ACVR1 (Alk2) selected from the group consisting of” followed by a Markush listing of the inhibitors. See MPEP 2173.05(h) for customary Markush language.
(iii) Claim 11 contains the trademark/trade name Rilutek®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe riluzole and, accordingly, the identification/description is indefinite.
(iv) Claim 16 recites the limitation “wherein the agent that modulates the ligand for ACVR1 (activin)” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim because claim 1, upon which claim 16 depends, does not recite either ACVR1 or reference a ligand that modulates ACVR1. This rejection could be addressed by amending claim 16 to depend upon 2, 3, 4, 5 or 6. In addition, claim 17 is hereby included in this rejection because it depends upon an indefinite claim without resolving the indefiniteness.
Claim Rejections - 35 USC § 112(a)
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 1-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating disease with LDN-212854, LDN-193189, dorsomorphin, REGN2477 and other known ACVR1 inhibitors, does not reasonably provide enablement for preventing neurodegeneration/demyelination or for treatment/prevention with any BMP receptor /ACVR1 inhibitors or modulators of ACVR1 ligands as broadly recited. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” (See In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 Fed. Cir. 1988). These factors include, but are not limited to: (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Claims 1, 2 and 4 (and relevant dependent claims) encompass preventing neurodegeneration and demyelination in the alternative. There is no guidance suggesting BMP pathway inhibition could prevent neurodegeneration or demyelination. The term prevention is generally understood as encompassing a total protection from disease or injury. Thus, given the high level of required effect, a high level of evidence showing prevention is also required. The prior art of Petersen et al. (Neuron, 2017; 96: 1003-1012—on IDS filed 12/05/2022) suggests that future studies focus on BMP receptor inhibitors as possible therapeutics to counteract demyelination in neurodegenerative disease (see paragraph bridging pages 1009-1010). The instant specification discloses that administering LDN-212854 “can promote myelin repair by overcoming abortive OPC [oligodendrocyte progenitor/precursor cells] differentiation at sites of neurovascular dysfunction”, and thereby “expand the toolbox of promyelinating drugs” (see pages 46, lines 16-19). The specification teaches that “LDN-212854 increased myelinating OLs and eliminated OPC differentiation to astrocytes” (see p. 47, lines 25-33), but is silent with respect to prevention of all pathological events following administration of LDN-212854.
Further, many of the neurodegenerative conditions characterized by neurodegeneration and encompassed by the claims are not preventable. For instance, Huntington's disease is an inherited autosomal dominant disorder, and cannot be prevented, nor its course reversed or halted. Regarding Parkinson’s disease and Alzheimer’s disease, a review by Van Bulck et al. (Int. J. Mol. Sci. 2019, 20, 719; doi:10.3390/ijms20030719; 36 pages total) notes that “no current therapies can prevent, slow, or halt progression” of neurodegenerative diseases (see abstract) and that “[neurodegenerative diseases are incurable and debilitating conditions that result in progressive degeneration and/or death of nerve cells,” (see p. 1, 1st sentence). Van Bulck et al. teach there are still no effective treatments currently available to reverse or prevent the course of neurodegenerative diseases (see p. 2, 1st full paragraph). Further, Lemere et al. (Rejuventation Res. 2006, 9(1):77-84) state that Alzheimer's disease is currently without an effective cure or preventive treatment (see abstract). Similarly, Hess et al. (US 2013/0116179 A1) teach that the effect of the current licensed pharmaceutical therapies is to reduce symptoms rather than to prevent the development of the disease (see [0005]). Thus, the relevant art recognizes the unpredictability of methods directed to preventing or even treating neurodegeneration.
Claims 1-6 and 8-16 are broad with respect to the recited BMP receptor inhibitors, ACVR1 inhibitors or agents that modulate the ligand(s) for ACVR1. Further, “modulate” encompasses both up- and down-regulation. Although the claims recite “the ligand for ACVR1, there is more than one ACVR1 ligand, and further, not all of the ligands have been identified. See Pacifici, (Cytokine & Growth Factor Reviews 27 (2016) 93-104), which states: “ALK2 [i.e., ACVR1] is able to bind several ligands in vitro such as BMP4, BMP6, BMP7, BMP9 and activins, but the identity and spectrum of its natural ligands in vivo are not clear” (p. 94, left column, 1st paragraph).
As noted above, the relevant art recognizes the unpredictability of treating and preventing neurodegeneration. The prior art teaches that certain known BMP/ACVR1 inhibitors may promote remyelination. For instance, see Karni et al. (WO 2013186777), who teach treating neurodegenerative diseases, including MS, Alzheimer’s disease, Parkinson’s disease and ALS, comprising administering a BMP inhibitor or BMP receptor antagonist, including dorsomorphin or LDN-193189 (claims 20-35). Also see Izrael et al. (WO 2015/186128), who teach methods of inducing myelination (re-myelination) in a patient suffering from demyelination from a disease that includes multiple sclerosis, comprising administering LDN-193189 (see claims 1-4). In addition, while the specification suggests BMP inhibition may “expand the toolbox of promyelinating drugs” (see pages 46, lines 16-19), this is not commensurate in scope with the claimed invention. However, patent protection is granted in return for an enabling disclosure, not for vague intimations of general ideas that may or may not be patentable. Tossing out the mere germ of an idea does not constitute an enabling disclosure. Reasonable detail must be provided in order to enable members of the public to understand and carry out the invention. See Genentech v. Novo Nordick A/S (CAFC) 42 USPQ2d 1001 (1997).
Due to the large quantity of experimentation necessary to generate BMP receptor inhibitors, ACVR1 inhibitors or modulators of ACVR1 ligands in order to treat or prevent neurodegeneration, promote remyelination, ameliorate/prevent demyelination or decrease differentiation of progenitors to astrocytes, the lack of direction/guidance presented in the specification regarding prevention of the recited conditions, the absence of working examples directed to the same, the complex nature of the invention, the unpredictability of treating/preventing neurodegeneration and demyelination, and the breadth of the claims which fail to recite limitations on the BMP receptor inhibitors, ACVR1 inhibitors or modulators of ACVR1 ligands, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Claims 1-6 and 8-16 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The claims are drawn to BMP receptor inhibitors, ACVR1 inhibitors or agents that modulate the ligand for ACVR1 in order to treat or prevent neurodegeneration, promote remyelination, prevent or ameliorate demyelination, enhance myelination and decrease differentiation of progenitors to astrocytes. Further, “modulate” encompasses both up- and down-regulation. Although the claims recite “the ligand for ACVR1, there is more than one ACVR1 ligand, and further, not all of the ligands have been identified (see Pacifici, cited above; p. 94, left column, 1st paragraph). To provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The MPEP states that for inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession (see MPEP 2163(II)(A)(3)(a)(i)). The methods reciting agents capable of treatment and prevention of neurodegeneration are part of an unpredictable and emerging technology (see Van Bulck et al., cited above; p. 2, 1st full paragraph).
In deciding whether the application complies with the written description requirement of 35 USC 112(a) or 35 USC 112 (pre-AIA ), first paragraph, it is necessary to understand what Applicant has possession of as well as what Applicant is claiming. From the specification, it is clear that Applicant has possession of a number of small molecule inhibitors of ACVR1 at pages 16-19, namely, LDN-212854, dorsomorphin, DMH1, saracatinib, BCX9250, KER-047, INCB000928, BLU-782, momelotinib, LDN-193189, K02288, LDN-214117, LDN-213844, M4K2009 and M4K2149. Further, regarding claim 16, which encompasses an antibody that modulates the ligand(s) for ACVR1, it is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. The instant specification discloses a single anti-activin antibody, namely, REGN2477. The species disclosed in the specification are not representative of the genus of BMP receptor inhibitors, ACVR1 inhibitors or agents that modulate (up- or down-regulate) the many ligands for ACVR1 and are capable of treating/preventing neurodegeneration, promoting remyelination, preventing/ameliorating demyelination, enhancing myelination and decreasing differentiation of progenitors to astrocytes. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). With the exception of the small molecule inhibitors of ACVR1, LDN-212854, dorsomorphin, DMH1, saracatinib, BCX9250, KER-047, INCB000928, BLU-782, momelotinib, LDN-193189, K02288, LDN-214117, LDN-213844, M4K2009 and M4K2149 and the antibody, REGN2477, the skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. 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. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, only LDN-212854, dorsomorphin, DMH1, saracatinib, BCX9250, KER-047, INCB000928, BLU-782, momelotinib, LDN-193189, K02288, LDN-214117, LDN-213844, M4K2009, MK2149 and REGN2477, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Notice for all US Patent Applications filed on or after March 16, 2013: 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.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-10 and 12-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Karni et al. (WO 2013186777). The claims encompass methods for treating neurodegeneration, promoting/enhancing remyelination in neurological diseases/disorders and ameliorating demyelination in a mammal or human comprising administering an effective amount of at least one bone morphogenetic protein (BMP) receptor, an ACVR1 (Alk2) inhibitor or an agent that modulates the ligand for ACVR1, wherein said ACVR1 inhibitor is, for example, LDN-193189 and wherein the mammal has been diagnosed with, for example, multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS). Karni et al. teach treating neurodegenerative diseases, including MS, Alzheimer’s disease, Parkinson’s disease and ALS, comprising administering a BMP receptor inhibitor, including dorsomorphin or LDN-193189 (claims 20-35), thereby meeting limitations set forth in claims 1-9.
Further, Karni et al. teach that when treating various neurodegenerative diseases, additional agents “may be required” (see p. 35, 3rd-6th paragraphs; p. 40, 2nd paragraph; claims 36 and 37). Karni et al. teach co-administering donepezil, galantamine, rivastigmine or memantine when treating Alzheimer’s disease, and co-administering pramipexole, ropinirole, selegiline or rasagiline when treating Parkinson’s disease (see p. 35, last paragraph), thereby meeting the limitations of claims 10 and 12. Karni et al. teach that the additional agent may be an anti-inflammatory agent for instance, glatiramer acetate, interferon-beta, natalizumab, fingolimod, mitoxantrone, dimethyl fumarate, teriflunomide or alemtuzumab (see p. 36, 2nd paragraph), thereby meeting limitations of claim 13. Karni et al. teach administering benztropine (see p. 31, 2nd paragraph; p. 36, 1st line), thereby meeting the limitations of claims 14 and 15.
Because Karni et al. teach administration of the same agents to ameliorate demyelination and treat various neurodegenerative conditions, including MS, Alzheimer’s disease, Parkinson’s disease and ALS, i.e., they teach treating the same patient population with the same agent, thus, the same clinically significant improvements as recited in claims 1-6 regarding treatment, promoting myelination and decreasing differentiation of progenitors to astrocytes, is inherent to their teachings (see Ex parte Novitski, 26 USPQ2d 1389 (BPAI 1993); see also Integra LifeSciences I Ltd. V. Merck KGaA, (DC SCalif) 50 USPQ2d 1846)). The treatment methods set forth in Karni et al. must, by definition, achieve the same clinically significant improvements as recited in claims 1-6 absent evidence to the contrary.
Claims 1-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Izrael et al. (WO 2015/186128). The claims encompass methods for treating neurodegeneration, promoting/enhancing remyelination in neurological diseases/disorders and ameliorating demyelination in a mammal or human comprising administering an effective amount of at least one bone morphogenetic protein (BMP) receptor, an ACVR1 (Alk2) inhibitor or an agent that modulates the ligand for ACVR1, wherein said ACVR1 inhibitor is, for example, LDN-193189 and wherein the mammal has been diagnosed with, for example, multiple sclerosis. Izrael et al. teach methods of inducing myelination (re-myelination) in a patient suffering from demyelination from a disease that includes multiple sclerosis, comprising administering an effective amount of an ACVR1/ALK2 receptor inhibitor to said patient, wherein said inhibitor is LDN-193189 (see claims 1-4). In addition, Izrael et al. contemplate treating human subjects (see p. 18, lines 1-2), thereby meeting the limitations of claims 1-9.
Because Izrael et al. teach administration of the same agents to ameliorate demyelination in those suffering from MS, they teach treating the same patient population with the same agent, thus, the same clinically significant improvements as recited in claims 1-6 regarding treatment, promoting myelination and decreasing differentiation of progenitors to astrocytes, is inherent to their teachings (see Ex parte Novitski, 26 USPQ2d 1389 (BPAI 1993); see also Integra LifeSciences I Ltd. V. Merck KGaA, (DC SCalif) 50 USPQ2d 1846)). The treatment methods set forth in Izrael et al. must, by definition, achieve the same clinically significant improvements as recited in claims 1-6 absent evidence to the contrary.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over Karni et al. (WO 2013186777—cited above) in view of Barber (WO2008039514). A statement regarding what the claims are drawn to is set forth above in the preceding rejections and is hereby incorporated. The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. Karni et al. teach treating neurodegenerative diseases, including MS, Alzheimer’s disease, Parkinson’s disease and ALS, comprising administering a BMP receptor antagonist, including dorsomorphin or LDN-193189 (claims 20-35), thereby meeting limitations set forth in claims 1-9. Further, Karni et al. teach that when treating various neurodegenerative diseases, additional agents “may be required” (see p. 35, 3rd-6th paragraphs; p. 40, 2nd paragraph; claims 36 and 37). Karni et al. teach co-administering donepezil, galantamine, rivastigmine or memantine when treating Alzheimer’s disease, and co-administering pramipexole, ropinirole, selegiline or rasagiline when treating Parkinson’s disease (see p. 35, last paragraph), thereby meeting the limitations of claims 10 and 12. Karni et al. teach administering benztropine (see p. 31, 2nd paragraph; p. 36, 1st line), thereby meeting the limitations of claims 14 and 15.
Karni et al. also teach that the additional agent may be an anti-inflammatory agent of the type used for treating MS, for instance, glatiramer acetate, interferon-beta, natalizumab, fingolimod, mitoxantrone, dimethyl fumarate, teriflunomide or alemtuzumab (see p. 36, 2nd paragraph), thereby meeting limitations of claim 13. Since Karni et al. explicitly teach treating MS and demyelinating diseases (see also p. 35, 2nd paragraph), it flows therefrom that their methods promote remyelination and ameliorate demyelination. Karni et al. also suggest this, disclosing that blockage of BMP2/4 may enhance remyelination (see p. 38, 1st paragraph; p. 60, last paragraph). In addition, the effects of administering an ACVR1 inhibitor (LDN-193189) are inherent in the methods taught by Karni et al. because they teach the same agent administered to the same patient population as recited in the claims. The recitation of the effects of the ACVR1 on the patient population are part of to the understandings and expectations disclosed in the prior art of Karni and colleagues. The method of treatment comprising administering LDN-193189 was part of the disclosure of the prior art, so the effects upon the body of the patients are inherent. Further, for the record, the express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 103. “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995) (affirmed a 35 U.S.C. 103 rejection based in part on inherent disclosure in one of the references). See also In re Grasselli, 713 F.2d 731, 739, 218 USPQ 769, 775 (Fed. Cir. 1983). See also MPEP 2112.
The second factor to consider is to ascertain the differences between the prior art and the instant claims. While Karni et al. disclose that the single approved medicine for ALS is riluzole (see paragraph bridging pages 31 and 32), they do not explicitly teach co-administering riluzole with dorsomorphin or LDN-193189. Barber teaches co-administering riluzole with their inventive compound in order to treat ALS (see claims 1-6). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to co-administer riluzole because even though it is not curative, it is the only approved medicine for treating ALS. The person of ordinary skill in the art would have been motivated to co-administer riluzole because ALS is “rapidly progressive [and] invariably fatal”, and co-administering it with other agents may improve its efficacy (see paragraphs [0015] and [0025] of Barber). There is also a normal desire of those having ordinary skill in the art to use all possible methods of treatment to treat such a devastating disease. Furthermore, the person of ordinary skill in the art could have reasonably expected success because Karni et al. suggest that “[a] person skilled in the art in the field of the invention (e.g. a physician) will know how to identify an "additional therapeutic agent" that will be suitable for the treatment of any of the… neurodegenerative disease[s] or CNS damage encompassed by the present disclosure”, and he or she would be aware that riluzole is the sole approved medicine available for treatment of ALS.
Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 1-10 and 12-16 are rejected under 35 U.S.C. 103 as being unpatentable over (WO 2013186777—cited above) in view of Gromada et al. (WO 2015017576). A statement regarding what the claims are drawn to is set forth above in the preceding rejections and is hereby incorporated. The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. Karni et al. teach treating neurodegenerative diseases, including MS, Alzheimer’s disease, Parkinson’s disease and ALS, comprising administering a BMP receptor antagonist, including dorsomorphin or LDN-193189 (claims 20-35), thereby meeting limitations set forth in claims 1-9. Further, Karni et al. teach that when treating various neurodegenerative diseases, additional agents “may be required” (see p. 35, 3rd-6th paragraphs; p. 40, 2nd paragraph; claims 36 and 37). Karni et al. teach co-administering donepezil, galantamine, rivastigmine or memantine when treating Alzheimer’s disease, and co-administering pramipexole, ropinirole, selegiline or rasagiline when treating Parkinson’s disease (see p. 35, last paragraph), thereby meeting the limitations of claims 10 and 12. Karni et al. teach administering benztropine (see p. 31, 2nd paragraph; p. 36, 1st line), thereby meeting the limitations of claims 14 and 15.
Karni et al. also teach that the additional agent may be an anti-inflammatory agent of the type used for treating MS, for instance, glatiramer acetate, interferon-beta, natalizumab, fingolimod, mitoxantrone, dimethyl fumarate, teriflunomide or alemtuzumab (see p. 36, 2nd paragraph), thereby meeting limitations of claim 13. Since Karni et al. explicitly teach treating MS and demyelinating diseases (see also p. 35, 2nd paragraph), it flows therefrom that their methods promote remyelination and ameliorate demyelination. Karni et al. also suggest this, disclosing that blockage of BMP2/4 may enhance remyelination (see p. 38, 1st paragraph; p. 60, last paragraph). In addition, the effects of administering an ACVR1 inhibitor (LDN-193189) are inherent in the methods taught by Karni et al. because they teach the same agent administered to the same patient population as recited in the claims. The recitation of the effects of the ACVR1 on the patient population are part of to the understandings and expectations disclosed in the prior art of Karni and colleagues. The method of treatment comprising administering LDN-193189 was part of the disclosure of the prior art, so the effects upon the body of the patients are inherent. Further, for the record, the express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 103. “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995) (affirmed a 35 U.S.C. 103 rejection based in part on inherent disclosure in one of the references). See also In re Grasselli, 713 F.2d 731, 739, 218 USPQ 769, 775 (Fed. Cir. 1983). See also MPEP 2112.
The second factor to consider is to ascertain the differences between the prior art and the instant claims. Karni et al. does not teach that the agent that modulates the ligand for ACVR1 (activin) is an antibody. Gromada et al. teach antibodies that bind activin A for the treatment of diseases associated with decreased muscle mass or strength, which includes MS, ALS and Parkinson’s disease (see abstract; paragraphs [0034] and [00115]; claims 34 and 35). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the teachings of Karni et al. by also administering an activin A antibody to treat MS, ALS or Parkinson’s disease as taught in Gromada et al. because these conditions are characterized by loss of muscle mass and strength and Gromada et al. provide methods for ameliorating conditions associated with decreased “muscle mass and strength” (see paragraph [0033]-[0034]). The person of ordinary skill in the art would have been motivated to treat conditions associated with loss of muscle with anti-activin antibodies because administration resulted in increased muscle in a mouse model (see p. 52 of Gromada and colleagues) and there is a motivation in the art to treat symptoms of these conditions, including muscle loss. For this reason, as well, the person of ordinary skill in the art could have reasonably expected success.
Thus, the claims do not contribute anything non-obvious over the prior art.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Karni et al. and Gromada et al. as applied to claims 1-10 and 12-16 above, and further in view of Latres et al. (Nature Communications 8: 15153; DOI: 10.1038/ncomms15153). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. The combined teachings of Karni et al. and Gromada et al. and how they meet the limitations of claims 1-10 and 12-15 are outlined above in the preceding rejection and are hereby incorporated. The second factor to consider is to ascertain the differences between the prior art and the instant claims. The combined teachings of Karni et al. and Gromada et al. do not explicitly teach the antibody is REGN2477. As with Gromada et al., Latres et al. teach that inhibition of activin A with anti-activin A antibodies is a viable co-therapy for muscle wasting conditions and specifically characterizes the anti-activin antibody, REGN2477 (see abstract; p. 2, right column.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the combined teachings of Karni et al. and Gromada et al. by using the activin antibody, REGN2477, as taught in Latres et al. because it represents a specific example of an equivalent anti-activin antibody that can be substituted in the methods of Gromada et al. Indeed, Latres et al. also teach that activin A inhibition with REGN2477 increased muscle force (see p. 4, Figure 2). The person of ordinary skill in the art would have been motivated to substitute REGN2477 because Latres et al. teach the same experimental results as disclosed in Gromada and colleagues, thus, the person having ordinary skill in the art would merely be substituting one known element for another to achieve predictable results. Furthermore, given the success in REGN2477 increasing muscle force in the experiments disclosed in Latres et al., the person of ordinary skill in the art could have reasonably expected success.
Thus, the claims do not contribute anything non-obvious over the prior art.
Conclusion
No claim is allowed.
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/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675