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 .
DETAILED ACTION
The amendment to the claims filed after non-final office action on May 21, 2025 is acknowledged.
Claims 10, 12, 15, 18 were canceled, claims 4, 8, 13 were amended, claims 23-27 were newly added and claims 1-9, 11, 13-14, 16-17, 19-27 are pending in the instant application.
The restriction was deemed proper and was made FINAL in this office action.
Claims 1-7, 11, 14, 16-17, 19-23, 25 (claims 23 and 25 are new) remain/are withdrawn from consideration as being drawn to a non-elected invention/species. Claim 23 is withdrawn as being drawn to a non-elected species as ALS is the elected species for disease and SEQ ID NO:3 is the elected species of compound.
Claims 8-9, 13, 24, 26-27 are examined on the merits of this office action.
Withdrawn Objections/Rejections
The objection of claims 8 and 13 are withdrawn in view of amendment of the claims filed May 21, 2025.
The rejection of claim 13 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of amendment of the claim filed May 21, 2025.
The rejection of claim 13 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, is withdrawn in view of amendment of the claim filed May 21, 2025.
Maintained/Revised Rejections
Claim Rejections - 35 USC § 112, first paragraph
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 8-9, 13, 24, 26-27 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 specific diseases neurodegenerative diseases associated with NMDA toxicity and TRPM4 with specific compounds, does not reasonably provide enablement for treating and/or preventing any neurodegenerative disease (including those listed in instant claim 13) with any of the compounds encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The Nature of the Invention/ The breadth of the claims
The claims are drawn to “A method for treating a neurodegenerative disease of the human or animal body involving NMDAR mediated toxicity, comprising administering a compound selected from the group consisting of: i) a polypeptide comprising a) SEQ ID NO:3, SEQ ID NO:4 and at most 200mer and ii) a fusion protein comprising the sequences of i) and at least one heterologous amino acid sequence. Claim 9 claims “administering a compound that is an inhibitor of NMDA receptor/TRPM4 complex formation” and Claim 13 is drawn to treating many different disease including neurodegenerative diseases. Claim 24 claims “treating a disease involving neurodegenerative events caused by NMDAR mediated toxicity….” Furthermore, the claims encompass the use of SEQ ID NO:4, which is defined with multiple variable residues and substitutions. The specification does not provide sufficient guidance to teach a PHOSITA which of these many sequence variants would be effective in treating the claimed disease.
The claims are broad with respect to the compound to be administered for treating any neurodegenerative disease involving NMDAR mediated toxicity which ranges from pain, Alzheimer’s, depression and a brain tumor and the peptides encompassed by the claims. Claim 13 further claim a laundry list of disease ranging from stroke, Alzheimer’s disease to brain tumor and HIV infection. Claim 24 claims diseases “involving neurodegenerative events caused by NDMAR mediator toxicity”. The claims are broad with respect to the patient population to be treated/neurodegenerative diseases to be treated.
The claims encompass a plethora of diseases with disparate causes and pathological processes, all under a single mechanistic umbrella. The breadth far exceeds the range of conditions actually tested or which detailed protocols are provided. The invention relies on interfering with TRPM4/NMDAR receptor complex formation using specific N-terminal TRPM4 sequences to inhibit NMDAR mediated toxicity. The claimed diseases span diverse etiologies-ischemic, neurodegenerative, infectious, psychiatric and neoplastic-with widely varying tissue and environments, pathophysiological cascades and therapeutic challenges. The effect of TRPM4 inhibition on NMDAR mediated toxicity in on disease state cannot be reliably predicted to translate to all others. Furthermore, the PHOSITA would be required to engage in undue experimentation both to determine which sequence variants function as intended and to apply them across the numerous disease contexts recite in the claims.
The State of the Prior Art
While NMDAR involvement is well documented for some conditions (e.g. stroke, traumatic brain injury), the therapeutic effect of TRPM4 peptide inhibition in these contexts is not established in the prior art, particularly for psychiatric, infectious, and tumor related conditions. The role of TRPM4 in modulating NMDAR-mediated toxicity across the breadth of claimed diseases is not part of the established knowledge in the art at the time of filing.
Guinamard (British Journal of Pharmacology (2014) 171 1600–1613, cited previously) discloses various small molecule inhibitors of TRPM4 including 9-phenanthrol, MPB-104 etc… (see Figure 1). Guinamard additionally teaches “The phenanthrene-derivative 9-phenanthrol is a recently identified inhibitor of the transient receptor potential melastatin (TRPM) 4 channel, a Ca2+ -activated non-selective cation channel whose mechanism of action remains to be determined. Subsequent studies performed on other ion channels confirm the specificity of the drug for TRPM4. In addition, 9-phenanthrol modulates a variety of physiological processes through TRPM4 current inhibition and thus exerts beneficial effects in several pathological conditions. 9-Phenanthrol modulates smooth muscle contraction in bladder and cerebral arteries, affects spontaneous activity in neurons and in the heart, and reduces lipopolysaccharide-induced cell death. Among promising potential applications, 9-phenanthrol exerts cardioprotective effects against ischemia-reperfusion injuries and reduces ischemic stroke injuries. In addition to reviewing the biophysical effects of 9-phenanthrol, here we present information about its appropriate use in physiological studies and possible clinical applications” (see abstract). Guinamard teaches the various ability of the compound to inhibit in different cell types including different cancer types (see Table 2). Additionally, the inhibitor can have various effects on different physiological processes (Table 3). Thus, clearly, different “TRPM4 inhibitors” can have varying, unpredictable effects on different tissue types and physiological processes. No one inhibitor that falls with the scope of the instant claim would have necessarily the same effects on the cell and thus, is unpredictable in the ability to treat ANY disease associated with NMDAR mediated toxicity.
The Predictability or Unpredictability of the Art/ The Relative Skill of Those in the Art
The prior art regarding treatment of specific conditions with specific TRPM4 inhibitors is limited and unpredictable (see above).
The relationship between TRPM4 inhibition and clinical improvement in diseases involving NMDAR-mediated toxicity is highly unpredictable. Even when NMDAR involvement is known, the relative contribution of TRMP4 to the pathological cascade, and the ability of the claimed peptides to reach and affect the relevant tissues in each disease, varies significantly. Even with a high level of skill in neuroscience and pharmacology, the unpredictability of TRPM4s role across this breadth of diseases and lack of specific teaching in the specification would require substantial experimental effort to determine therapeutic applicability in each disease.
It is not the skill of those in the art to treat neurodegenerative disease or disorder/events (or those listed in instant claim 13) with one compound or any compound that inhibits NMDA/TRPM4 complex.
Amount of Guidance/ The Presence or Absence of Working Examples
Applicant’s reduce to practice the following: Example 2 shows knockdown of TRPM4 protects neurons from NMDA receptor mediate toxicity (shRNAS); Example 3: The N-Terminal Domain of Mouse TRPM4 Contains a Sequence which is Neuroprotective if Expressed in HEK293 Cells (SEQ ID NO:47, SEQ ID NO:5 being most protective); A Variant of the Sequence of SEQ ID NO:5 also Reduces NMDA Receptor-Mediated Cell Toxicity (see Example 5, two Phe substituted with Tyr); use of a fusion comprising SEQ ID NO:5 for treating NMDA toxicity (Example 6); Example 10 discloses “virtual screening for compounds that bind SEQ ID NO:5 in Mouse TRPM4); Table 2 and Example 11 discloses potential candidate compounds; lastly Example 17 discloses use of two small molecule compounds on TRPM4 function. Thus, it appears the results/findings were based off of the sequence of SEQ ID NO:5 (an n-terminal sequence of TRPM4) and small molecules compounds that target this sequence.
The specification describes in detail in vitro NMDA excitotoxicity assays, a mouse MCAO ischemia model, and retinal NMDA injection injury. No examples, dosing strategies, delivery routes or efficacy data are provided for the majority of the claimed diseases, especially those outside of CNS ischemia models. The disclosure does not instruct the skilled artisan on how to adapt the invention to treat each disease without substantial further research.
Working examples are limited to rodent models of acute NMDA induced neuronal injury and ischemia. No in vivo or in vitro disease models are provided for infectious conditions, psychiatric conditions, neurodegenerative diseases beyond ischemia or cancer.
The Quantity of Experimentation Necessary
To practice the invention for each listed disease a person of ordinary skill in the art would need to develop or identify disease specific models, establish whether TRMP4/NMDAR complex inhibition is a significant driver of pathology in that context, determine effective dosing and delivery, evaluate safety and off target effects for that disease. This is more than routine optimization and one would be burdened with undue experimentation.
The disclosure enables treatment of a narrow subset of the claimed diseases (e.g. stroke, acute excitotoxicity injury) but does not enable treatment of the full scope of diseases in claim 13 with undue experimentation. While Applicant’s citations may show that NMDAR-mediated toxicity is implicated in certain additional conditions, they do not provide enabling guidance for applying the claimed TRPM4 peptide therapy to those diseases. A person of ordinary skill would therefore be required to engage in undue experimentation to practice the invention across its full scope. Accordingly, the rejection under 35 U.S.C. 112(a) is maintained.
Response to Applicant’s Arguments
Applicant argues the prior art cited did not disclose the TRPM4/NDMAR complex requirement for excitotoxicity because this was a novel discovery of the present application. Applicants assert Guinimard reference (9-phenathrol) is irrelevant and the effects were not unpredictable as 9-phenanthrol did not even inhibit TRPM4 directly but interfered differently. Applicant argues their invention uses N-terminal peptides acting as decoy for TRPM4/NMDAR (see Pages 10-11).
Applicant’s arguments have been fully considered but not found persuasive. While Applicant distinguishes Guinimard mechanistically, the citation was not presented as an anticipation reference but rather as evidence of the unpredictability in modulating TRPM4 activity. The fact that different TRMP4 inhibitors act through different mechanism underscores the complexity and variability of TRPM4 modulation in different disease contexts. Enablement does not require identical prior art compounds but requires that the disclosure provided sufficient teaching across the claimed scope despite variability.
Applicant argues that the Examiner asserted treatment/prevention of diseases like Alzheimer’s is unpredictable. Applicant argues prevention is no longer in the claims. FDA has already approved NMDA antagonists (memantine) for Alzheimer’s showing art is not wholly unpredictable (see Page 12 of Arguments).
Applicant’s arguments have been fully considered but not found persuasive. The approval of memantine does not demonstrate predictability for the specific TRPM4/NMDAR decoy peptides, which have a different structure, mechanism and delivery profile than small molecule NMDA antagonists. Even with memantine, efficacy in neurodegenerative disease such as Alzheimer’s remains limited and inconsistent, reflecting continued unpredictability in the art. Thus, the existence of an NMDA antagonist on the market does not relieve Applicant of burden to enable the use of TRPM4 peptides across the diverse claimed diseases.
Applicant argues that the specification provides sufficient guidance including multiple examples (SEQ ID NO:51, stroke, NMDA injury, retinal injury). Applicants states that the data show neuroprotection, demonstrating that blocking TRPM4/NMDAR is effective in vivo and that PHOSITA could reasonably apply the peptides to other mammals and other diseases with NMDAR involvement without undue experimentation. Applicants argue that the rodent examples utilized are representative of broader “neurodegenerative diseases” (see pages 13-14).
Applicant’s arguments have been fully considered but not found persuasive. The disclosed working examples are limited to acute excitotoxicity an ischemia models in rodents. No disclosure is provided for infectious, psychiatric, chronic neurodegenerative, or neoplastic disease, which involve distinct and more complex pathogenic pathways. A person of ordinary skill in the art would not reasonably extrapolate from acute stroke models to conditions such as schizophrenia, glioma, or HIV encephalopathy without substantial disease specific experimentation. Thus, the working examples do not adequately support the breadth of the claims.
Applicants further claim numerous pre-filing references to show that all claimed diseases involve NMDAR mediated toxicity. In particular the Examples include Stroke, AD, ALS, HD, TBI, MS-glutamate excitotoxity well document; Epilepsy, optic nerve disease, diabetic retinopathy, glaucoma-elevated glutamate, NMDA receptor involvement; Psychiatric (schizophrenia, depression)-ketamine, NMDA antagonists; Infectious (HIV, Malaria, Zika, toxoplasmosis, viral encephalitis)-show glutamate/NMDAR involvement in neurotoxicity; Brain tumors-glutamate release drives glioma progression. Applicants state that each disease has a mechanistic nexus to NMDAR toxicity and thus is enabled (see all pages 15-19).
Applicant’s arguments have been fully considered but not found persuasive. The cited references may establish that NMDAR activity is associated with each disease, but association is not equivalent to an enabling disclosure. None of the references provided demonstrate that TRPM4 peptides (as opposed to small molecules, general antagonists, or unrelated modulators) provide therapeutic effect in these diverse conditions. Enablement requires that he claimed method be practicable without undue experimentation across the scope, not simply that a mechanistic nexus exists. Although applicant asserts that the claimed diseases involve the same mechanism of pathogenesis, the art shows that NMDAR-mediated toxicity manifests differently depending on disease context cell type etc.. A person of ordinary skill in the art would still be required to conduct substantial disease specific experimentation to determine whether TRPM4/NMDAR decoy peptides would be effective in each condition. This exceeds routine optimization and constitutes undue experimentation. Accordingly, while the nexus references may support plausibility, this does not equate to enablement. The specification does not provide sufficient teaching to allow a PHOSITA to practice the invention across the entire scope of the claims.
Applicant further argues that years of experimentation would not be needed. Applicant argues that the combination of the stroke/MCAO model data and the nexus across diseases would allow a person of ordinary skill in the art to reasonably extend teachings to other diseases (see pages 20-22).
Applicant’s arguments have been fully considered but not found persuasive. This issue at hand is not the time required, but the amount and scope of experimentation needed to apply the invention across dozens of heterogenous diseases. Each disease would require distinct models, dosing regiments, delivery methods and efficacy assessment. This is not routine optimization but rather extensive, disease specific experimentation. Under In Re Wands, such breadth coupled with limited examples constitutes undue experimentation.
New Rejection
Claim Rejections - 35 USC § 112
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.
Claim 13 is 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.
Claim 13 is dependent on claim 8 and claims “The method of claim 8, wherein the neurodegenerative disease involving NMDAR mediated toxicity is selected from the group consisting of stroke, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), traumatic brain injury, multiple sclerosis, glutamate induced excitotoxicity, dystonia, epilepsy, optic nerve disease, diabetic retinopathy, glaucoma, pain, viral encephalopathy, vascular dementia, microangiopathy, Binswanger's disease, cerebral ischemia, hypoxia and Parkinson's disease, schizophrenia, depression, cerebral malaria, toxoplasmosis-associated brain damage, HIV infection-associated brain damage, Zika virus infection-associated brain damage and a brain tumor.”
The term “neurodegenerative disease” has a well-understood meaning in the art, referring to progressive disorders characterized by loss of structure or function of neurons, such as Alzheimer’s, Parkinson’s, Huntington’s or ALS. However, claim 13 includes conditions that are not neurodegenerative by conventional medical definition, including but not limited to: stroke/cerebral ischemia/hypoxia/TBI (acute vascular traumatic events, not progressive neurodegenerative diseases); infectious disease (HIV-associated brain damage, Zika virus brain damage, cerebral malaria, toxoplasmosis, viral encephalopathy); neoplastic disease (brain tumor); broad categories without clear diagnostic boundaries (pain, optic nerve disease). Because the claim prefaces the list with “neurodegenerative disease” but then enumerates conditions that a person of ordinary skill in the art would not classify as neurodegenerative (i.e. depression), the scope of the claim is internally inconsistent and ambiguous. A skilled artisan cannot determine with reasonable certainty whether these conditions are intended to fall within the scope of the claim.
Conclusion
No claims are 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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/E.R.D/ Examiner, Art Unit 1654
/JULIE HA/ Primary Examiner, Art Unit 1654