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 .
Election/Restrictions
Applicant’s species election without traverse of 7,7,10,10,13,13-D6-arachidonic acid in the reply filed on 3/17/2026 is acknowledged.
Applicants amended of claims 1, 2, 4 and 9-19 is acknowledged.
Applicant’s withdrawing of claims 5-7 is acknowledged.
There are no new claims.
Furthermore, the Examiner initiated an interview on 6/15/2026 for clarification regarding applicant’s election of species for neurodegenerative disease. In response to Examiner’s interview, applicant’s election of species for neurodegenerative disease on 6/16/2026 of “amyotrophic lateral sclerosis” without traverse is acknowledged.
Claims 1-4, and 8-19 are under consideration in this office action and will be examined on the merits.
Status of Claims
Claims 1-19 are pending. Applicant amended claims 1, 2, 4, and 9-19. Claims 5-7 are withdrawn.
Claims 1-4 and 8-19 are under consideration in the instant office action.
Claim Objections
Claims 2 and 14 are objected to because of the following informalities:
In claims 2 and 14, the disease progressive supranuclear palsy (PSP) is spelled progressive supernuclear palsy (PSP).
Appropriate correction(s) are required.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1-2, 11, 14, and 17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 22-23 of US Patent No. 11,491,130 and claims 1, 3, 13, and 27of US Patent No. 11,351,143. Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets recite similar subject matter with significant overlapping of multiple claims. For example;
Claim 1 of ‘130 recites method for reducing disease progression of a neurodegenerative disease treatable with 11,11-D2-linoleic acid in an adult patient, the method comprising: administering 11,11-D2-linoleic acid or an ester thereof to the patient with a dosing regimen that comprises a primer dose and a maintenance dose thereby reducing said disease progression in said patient, wherein: a) said primer dose comprises periodic administration at least about 7 to 12 grams of 11,11-D2-linoleic acid or an ester thereof per day, wherein said primer dose is continued for at least about 30 days to rapidly achieve a therapeutic concentration of 13,13-D2-arachidonic acid in vivo; and b) subsequent to the completion of the primer dose, periodically administering said maintenance dose of no more than about 65% of the primer dose of 11,11-D2-linoleic acid or an ester thereof per day thereof to maintain said therapeutic concentration of 13,13-D2-arachidonic acid in vivo, such that the rate of disease progression is reduced, wherein the neurodegenerative disease is mediated at least in part by lipid peroxidation of polyunsaturated fatty acids in neurons of the patient which is also encompassed by instant claims 1, 11 and 17.
Claim 2 of ‘130 recites wherein said neurodegenerative disease is amyotrophic lateral sclerosis, Huntington's Disease, progressive supernuclear palsy (PSP), APO-e4 Alzheimer's Disease, corticobasal disorder (CBD), frontotemporal dementia (FTD), nonfluent variant primary progressive aphasia (nfvPPA), other tauopathies, or late onset Tay-Sachs which is also encompassed by instant claims 2 and 14.
Similarly, claim 1 of ‘143 recites a method for reducing disease progression of ALS in a patient, the method comprising: administering 11,11-D2-linoleic acid or an ester thereof to the patient with a dosing regimen that comprises a primer dose and a maintenance dose thereby reducing said disease progression in said patient, a) said primer dose comprises about 9 grams of 11,11-D2-linoleic acid or an ester thereof per day wherein said primer dose is continued for about 30 days to 45 days to rapidly achieve a therapeutic concentration of 13,13-D2-arachidonic acid in vivo due to hepatic conversion of a portion of said 11,11-D2-arachidonic acid to 13,13-D2-arachidonic acid thereby reducing the rate of disease progression; and b) subsequent to the about 30 days to 45 days of administering said primer dose, administering said maintenance dose of about 5 grams of 11,11-D2-linoleic acid or an ester per day thereof to maintain said therapeutic concentration of 13,13-D2-arachidonic acid in vivo such that the rate of disease progression is reduced provided that said reduction is measured to be at least about 30% reduction relative to the rate of disease progression during the natural history of the patient.
Claim 3 of ‘143 recites wherein a percent reduction in the rate of disease progression is determined by: measuring a natural rate of disease progression in a patient or an average natural rate of disease progression in a cohort of patients; measuring the rate of disease progression in said patient or cohort of patients during a period of compliance with the administering step; and calculating the difference between the natural rate and the rate during the period of compliance, dividing the difference by the rate of disease progression during the natural history of the patient, and multiplying by 100.
Therefore, instant claims 1-2, 11, 14, and 17 130 are an obvious variation of claims 1-12 and 22-23 of ‘130 and instant claims 1-2, 4, 11, 14, and 19 are obvious variation of claims 1, 3, 13, and 27 of ‘143.
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 1-4 and 8-19 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 a method for treating amyotrophic lateral sclerosis in a patient comprising administering to the individual an effective amount of a deuterated arachidonic acid, does not reasonably provide enablement for “Huntington's Disease, progressive supernuclear palsy (PSP), Friedreich's ataxia, APO-e4 Alzheimer's Disease, corticobasal disorder (CBD), frontotemporal dementia (FTD), nonfluent variant primary progressive aphasia (nfvPPA), other tauopathies, and late onset Tay- Sachs.” using “an effective amount of a deuterated arachidonic acid, an ester thereof, or a prodrug thereof, to reduce the disease progression in the patient” across plethora of neurodegenerative diseases listed in claims 2, and 14.
Additionally, the specification does not reasonably provide enablement for particular dosage amounts, administration routes, and pharmacokinetic properties. 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.
The claims recite, inter alia, method of “reducing neurodegenerative disease progression in a patient, the method comprising: administering an effective amount of a deuterated arachidonic acid, an ester thereof, or a prodrug thereof, to reduce the disease progression in the patient” over extremely broad dosing regimen, and disease-types.
Claim 1 recites broadly a method encompassing treatment, reducing neurodegenerative disease progression in a patient, using an effective amount of a composition comprising “a deuterated arachidonic acid, an ester thereof, or a prodrug thereof”.
Claim 2 extends the method of claim 1 to a wide spectrum of etiologically distinct neurodegenerative disorders (amyotrophic lateral sclerosis, Huntington's Disease, progressive supernuclear palsy (PSP), Friedreich's ataxia, APO-e4 Alzheimer's Disease, corticobasal disorder (CBD), frontotemporal dementia (FTD), nonfluent variant primary progressive aphasia (nfvPPA), other tauopathies, and late onset Tay- Sachs).
The specification provides enabling data for only a narrow subset of deuterated arachidonic acid (primarily D2-LA, D2-AA and D6-AA) in specific mice models and very limited patient population spanning from 1-3 patients. It identifies how to measure D6-AA in blood (example1, [0084]) that utilizes D2-AA as a proxy correlation between concentrations in CSF and in RBC’s. Example 2 evaluates the impact of D2-AA relative to D6-AA for controlling LPS induced inflammation leading to neurodegenerative diseases [0091], but these examples do not provide established regimens for reducing neurodegenerative disease progression using specific D2-AA and D6-AA.
Accordingly, the claims are far broader than what is actually taught and reasonably predictable, particularly as to reduction in neurodegenerative disease progression across all claimed disease types.
The instant specification fails to provide information that would allow the skilled artisan to practice the instant invention. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
Nature of the Invention:
The instant invention relates to therapeutic methods for serious, complex neurodegenerative diseases, which is a highly unpredictable and sophisticated field. The field is complex and relatively unpredictable for several reasons:
Neurodegenerative disease progression and therapeutic outcomes are influenced by multifactorial pathophysiology, genetics, comorbidities, and environmental factors (Sambra, Verónica et al. “Docosahexaenoic and Arachidonic Acids as Neuroprotective Nutrients throughout the Life Cycle.” Nutrients vol. 13,3 986. 18 Mar. 2021).
AA and its metabolites have dual role in neuroinflammation and neuroprotection; for example, AA metabolites can promote acute inflammatory responses via prostaglandins and thromboxanes and can increase Aβ production and plaque burden in Alzheimer’s models (Amtul, Zareen et al. “Detrimental effects of arachidonic acid and its metabolites in cellular and mouse models of Alzheimer's disease: structural insight.” Neurobiology of aging vol. 33,4 (2012)).
Changing membrane PUFA composition may have disease-specific and context-dependent effects that cannot be uniformly predicted from ALS data alone (Sambra, Verónica et al. “Docosahexaenoic and Arachidonic Acids as Neuroprotective Nutrients throughout the Life Cycle.” Nutrients vol. 13,3 986. 18 Mar. 2021).
Given this complex and somewhat unpredictable nature, the specification’s limited data (largely ALS-focused and animal inflammation models) do not reasonably support extrapolation of therapeutic efficacy to the entire genus of neurodegenerative diseases claimed.
The State of the Prior Art:
At the time of filing, the state of the art as reflected below included multiple approaches to treating inflammatory conditions:
Deuterated PUFAs such as RT001 (deuterated ethyl linoleate) are recognized as investigational agents hypothesized to reduce lipid peroxidation and motor neuron degeneration in ALS and other neurogenerative diseases. (Zesiewicz, T., Heerinckx, F., De Jager, R., Omidvar, O., Kilpatrick, M., Shaw, J. and Shchepinov, M.S. (2018), Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia. Mov Disord., 33: 1000-1005).
A phase I/II trial in Friedreich's ataxia with ST001 (1.8 or 9 g/day) demonstrated safety and tolerability as well as modest early signals (improved peak workload over 28 days), but concluded that further research was warranted (Weemering, Daphne N et al. “A randomized, double-blind, placebo-controlled phase 2 study to assess safety, tolerability, and efficacy of RT001 in patients with amyotrophic lateral sclerosis.” European journal of neurology vol. 30,12 (2023): 3722-3731).
A phase 2 ALS trial with RT001 over 24 weeks reported that RT001 was safe and well tolerated, with exploratory efficacy trends favoring RT001, but emphasized that larger trials are needed to evaluate efficacy. (Weemering, Daphne N et al. “A randomized, double-blind, placebo-controlled phase 2 study to assess safety, tolerability, and efficacy of RT001 in patients with amyotrophic lateral sclerosis.” European journal of neurology vol. 30,12 (2023): 3722-3731).
Thus, at the time of filing, while the prior art supports that deuterated PUFAs are promising but still investigational, with limited early clinical data in ALS and FA, not established standard therapies across multiple neurodegenerative diseases. The prior art therefore does not fill the gaps in the present disclosure; instead, it underscores the need for detailed, disease-specific clinical evidence to support the broad genus claimed.
The Relative Skill of those in the Art:
The level of skill in the art is a neuro-oncologist or clinician with a Ph.D., and/or an M.D.
The Predictability or Lack thereof in the Art:
As noted under the nature of the invention:
The art of treating neurodegenerative diseases is highly unpredictable; many candidate therapies with strong preclinical data fail in clinical trials. (Sambra, Verónica et al. “Docosahexaenoic and Arachidonic Acids as Neuroprotective Nutrients throughout the Life Cycle.” Nutrients vol. 13,3 986. 18 Mar. 2021)
Even with one disease (ALS), the RT001 phase 2 trial shows only exploratory trends and no definitive efficacy, despite prior promising mechanistic hypotheses. (Weemering, Daphne N et al. “A randomized, double-blind, placebo-controlled phase 2 study to assess safety, tolerability, and efficacy of RT001 in patients with amyotrophic lateral sclerosis.” European journal of neurology vol. 30,12 (2023): 3722-3731.)
AA and its metabolites can have opposing roles - contributing to neuroprotection in some contexts and exacerbating pathology in others (e.g., AD models with AA supplementation show increased Aβ and plaque formation). (Amtul, Zareen et al. “Detrimental effects of arachidonic acid and its metabolites in cellular and mouse models of Alzheimer's disease: structural insight.” Neurobiology of aging vol. 33,4 (2012)).
Given this unpredictability, extrapolating ALS-related examples and an LPS-lung-inflammation mouse model to broad, reliable clinical efficacy in Huntington’s disease, progressive supernuclear palsy (PSP), Friedreich's ataxia, APO-e4 Alzheimer's Disease, frontotemporal dementia (FTD), and late onset Tay- Sachs is not justified without extensive empirical work.
The Breadth of the Claims:
Claims 1, 2 and 14 are broad along multiple axes:
Chemical breadth: Claims cover any deuterated AA, its esters, or prodrugs, with generalized dosing ranges and therapeutic thresholds.
Disease and indication breadth: Claims encompass “neurodegenerative disease” broadly, with explicit recitation of amyotrophic lateral sclerosis, Huntington's Disease, progressive supernuclear palsy (PSP), Friedreich's ataxia, APO-e4 Alzheimer's Disease, corticobasal disorder (CBD), frontotemporal dementia (FTD), nonfluent variant primary progressive aphasia (nfvPPA), other tauopathies, and late onset Tay- Sachs.
Claims require at least about a 30% reduction in disease progression relative to natural history for any of these diseases.
In contrast, the enabling disclosure is essentially focused on:
Limited clinical data for D2-LA in ALS and FA; no clinical data for D6-AA in any disease. (Zesiewicz, T., Heerinckx, F., De Jager, R., Omidvar, O., Kilpatrick, M., Shaw, J. and Shchepinov, M.S, Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia. Mov Disord., 33: 1000-1005 (2018)).
Mechanistic speculation tying all neurodegenerative diseases to lipid peroxidation, despite prior art showing complex and sometimes deleterious roles of AA and its metabolites in disease such as Alzheimer’s disease. (Thomas MH, Pelleieux S, Vitale N and Olivier JL. Arachidonic acid in Alzheimer’s disease, J Neurol Neuromedicine (2016) 1(9): 1-6))
Accordingly, the breadth of the claims is not commensurate with the scope of the enabling disclosure. The breadth of these claims far exceeds the limited examples and data actually provided in the specification.
As such, the breadth of the claims is great.
The Amount of Direction or Guidance Presented:
Although the specification contains general guidance e.g.,
Structural definition of deuterated AA (D6AA) and its esters, with deuteration patterns on bis-allylic positions (7, 10, 13).
Dosing ranges for ALS-oriented primer/loading doses (0.5-5 g/day for 24-25 days) and maintenance doses (30-70% of primer).
Correlation of RBC D-AA percentages (at least about 0.5-3%) to “therapeutic concentration” in neurons.
General suggestions to restrict PUFA intake to favor D-AA incorporation.
However, specific guidance is lacking or purely speculative for many claimed diseases:
No concrete dosing regimens, RBC thresholds, or PK/PD targets are given for Huntington's Disease, progressive supernuclear palsy (PSP), Friedreich's ataxia, APO-e4 Alzheimer's Disease, corticobasal disorder (CBD), frontotemporal dementia (FTD), nonfluent variant primary progressive aphasia (nfvPPA), other tauopathies, and late onset Tay- Sachs.
The specification extrapolates ALS-based RBC thresholds to all neurodegenerative diseases without presenting any data or disease-specific rationale.
Prior art RT001/FA, as discussed above, shows limited early signals of efficacy in FA over 28 days, and emphasizes the need for further research, not established therapeutic dosing. A phase 2 ALS trial with RT001 likewise reports exploratory trends without definitive efficacy, underscoring that the clinical dose-response relationships are still investigational (Zesiewicz, T., Heerinckx, F., De Jager, R., Omidvar, O., Kilpatrick, M., Shaw, J. and Shchepinov, M.S, Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia. Mov Disord., 33: 1000-1005 (2018)).
Given the heterogeneity of disease mechanisms, this generic guidance is insufficient to enable a skilled artisan to achieve the claimed less than or equal to 30% reduction in progression in each disease without substantial de novo experimentation.
The Presence or Absence of Working Examples and Quantity of Experimentation:
Working examples in the specification are limited:
Example 1: Single patient receiving a 9g/day D2-LA; measurement of D2-AA in RBCs and CSF, supporting a correlation between RBC and CSF levels.
Example 2: Murine LPS-induced lung inflammation model showing D6-AA yields greater reduction in interalveolar space than D2-AA or non-deuterated AA/LA, indicating enhanced anti-inflammatory effects.
Comparative Example A/B: Small ALS cohorts treated with D2-LA (9g then 5g) with approx. 46% and 90% reduction in ALSFRS-R decline versus natural history.
Absent examples:
No actual human dosing or outcome data for D6-AA itself in ALS or any other neurodegenerative disease.
No examples at all for Huntington's Disease, progressive supernuclear palsy (PSP), Friedreich's ataxia, APO-e4 Alzheimer's Disease, corticobasal disorder (CBD), frontotemporal dementia (FTD), nonfluent variant primary progressive aphasia (nfvPPA), other tauopathies, and late onset Tay- Sachs
To practice the claimed methods for each disease (ALS, Huntington's Disease, progressive supernuclear palsy (PSP), Friedreich's ataxia, APO-e4 Alzheimer's Disease, corticobasal disorder (CBD), frontotemporal dementia (FTD), nonfluent variant primary progressive aphasia (nfvPPA), other tauopathies, and late onset Tay- Sachs), a skilled artisan would need to
Establish disease-specific natural history baselines and validated progression scales (e.g., ALSFRS-R for ALS, UHDRS for Huntington’s, PSP Rating scale, MMSE or CDR-SB for Alzheimer’s, FARS for FA, etc.).
Perform dose-finding and PL/PD studies for D6-AA or its prodrugs in each disease population to define “therapeutic concentration” thresholds in RBCs and neurons.
Conduct controlled clinical trials in each indication to demonstrate approx. 30% reduction in progression versus natural history, including controlling dietary PUFA intake as required by the specification.
Given that the working examples in the instant application are confined to a narrow murine context and cohort of only 3 patients. Therefore, coupled with the absence of human data for the specific D6-AA, indicates that the claims are broader than what has actually been reduced to practice. Consequently, they do not reasonably enable the full clinical breadth of the claims1-4 and 8-19.
To enable the full claim scope of claims 1-4 and 8-19, a skilled artisan would have to engage in extensive, iterative, unduly burdensome clinical experimentation to implement “an effective amount of a deuterated arachidonic acid, an ester thereof, or a prodrug thereof, to reduce the disease progression in the patient” across all claimed neurodegenerative diseases, routes, vehicles, and dosing regimens that are very large. To implement the claimed methods for each neurodegenerative disease listed, the skilled artisan would have to conduct extensive, case-by-case experimentation to determine:
Safe and effective therapeutic doses for each neurodegenerative disease in humans;
Appropriate formulation for each type of AA;
Specific dosing regimens and treatment durations for each underlying disease state; and
Whether LA and AA modulation and clinical benefit generalize beyond the particular mice strain and 3 members of the cohort, out of whom, one patient passed away during the comparative study.
This level of trial-and-error analysis, across many disease etiologies, goes well beyond routine optimization and constitutes undue experimentation.
Note that lack of a working example, is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP 2164. Genentech, Inc. v. Novo Nordisk, 108 F.3d at 1366, states that "a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable". Therefore, in view of the Wands factors, e.g., the amount of direction or guidance provided, absence of working examples, and the predictability of the art discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation in order to practice invention based on the details provided and scope of invention defined in claims 1-4 and 8-19.
Consequently, 1-4 and 8-19 are rejected for lacking scope of enablement.
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 1-4, 8-10, and 14 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.
Regarding claim 1, the phrase "effective amount" at line 3 renders the claim indefinite, because PHOSITA could not determine specific values for the amount based on the disclosure. See MPEP § 2173.05(c)(III). For example, see above enablement rejection regarding guidance provided and unpredictability in the art.
With respect to dependent claims 3, 9 and 15, although the claims recite “the therapeutic concentration of deuterated arachidonic acid is determined by its concentration in red blood cells,” there is no guidance in the specification as to which dose(s) would be appropriate for which neurodegenerative disorder. Consequently, what is an “effective amount” in the context of the claimed method is ambiguous and cannot be ascertained reasonably by PHOSITA.
Regarding claim 2 and 14, the claims are indefinite because they state that the disease is several diseases at the same time. For the purposes of examination and in light of applicant’s remarks selecting ALS, it is understood that the claim was likely meant to recite “one of “.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3 and 8-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Molinari et al. (“STABILIZED POLYUNSATURATED COMPOUNDS AND USES THEREOF”, Pub. No.: WO2019/204582A1; Pub. Date: Oct. 24, 2019) herein referred to as Molinari as evidenced by Alayash, Abdu I. “Hemoglobin Oxidation Reactions in Stored Blood.” Antioxidants (Basel, Switzerland) vol. 11,4 747. 8 Apr. 2022 and Centers for Disease Control and Prevention. Principles of epidemiology, 2nd ed. Atlanta: U.S. Department of Health and Human Services;1992
Regarding claim 1, Molinari teaches treating neurodegenerative disease, neuropathy and reducing disease progression in a patient with substituted PUFAs (Polyunsaturated fatty acids) (0004, 0010, 0052, 0072, 0073, and 0156). Molinari teaches the compound is a deuterated polyunsaturated fatty acid, or an ethyl ester thereof (Abstract). Molinari teaches that the omega-6 fatty acid is gamma linolenic acid, di homo gamma linolenic acid, arachidonic acid [0115]. Molinari teaches deuterated arachidonic acid [0112, claim 19] as depicted below:
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[0126]. Molinari teaches the substituted compound comprises an isotopically modified polyunsaturated fatty acid, isotopically modified polyunsaturated fatty acid ester, or isotopically modified polyunsaturated fatty acid pro-drug [0097, 0139-0140]. Molinari teaches the substituted compounds may be readily incorporated into cell membranes and may prevent, delays, or reverse lipid peroxidation and the oxidative damage caused by Lipid peroxidation (LPO) which is a self-propagating, free-radical chain reaction that amplifies toxic triggering effects in a variety of neurodegenerative conditions [0010]. Molinari teaches reduction of disease progression, clinical examination at 3 months showed no progression of disease since the start of the trial [0159]. Molinari teaches stabilization of progression and clear reversals of disease [0161]. Molinari discusses that the subject has or is at risk for at least one of neuropathy or a neurodegenerative disease and the amount of the substituted compound is effective to prevent, ameliorate or inhibit the progression of neuropathy or the neurodegenerative disease [0072]. Molinari teaches detecting the steady state plasma level of the substituted compound, or the level of the substituted compounds within red blood cell membrane to determine the incorporation level of the substituted compound [0086], and deuterated arachidonic acid was observed as present in the plasma at 0.6% and 3.0% of total arachidonic acid [0159]. While Molinari discusses therapeutic concentration in RBCs, it does not specifically mention therapeutic concentration in “motor neurons” or, threshold of “at least about 30% reduction relative to rate of disease progression during the natural history of the patient” as a formal limitation. Molinari teaches wherein a therapeutic concentration of deuterated arachidonic acid (para [0109], a cell or tissue of the patient maintains a sufficient concentration of the deuterated fatty acid or fatty acid ester to prevent or reduce autoxidation) is sufficient to reduce disease progression (para [0159], clinical examination at 3 months showed no progression of disease since the start of the trial). Based on Molinari’s teachings, one of ordinary skill in the art would have at once envisaged detection of the claimed substituted compounds within motor neurons as they are cells within the nervous system of the humans that undergo oxidation just like red blood cells or erythrocytes, largely because their high metabolic rate produces reactive oxygen species as a byproduct. In fact, RBCs are among the most vulnerable cells to oxidative stress in the entire human body (Alayash, Abdu I. “Hemoglobin Oxidation Reactions in Stored Blood.” Antioxidants (Basel, Switzerland) vol. 11,4 747. 8 Apr. 2022). (see In re Petering, 301 F.2d 676, 133 USPQ 275 (CCPA 1962) and In re Schauman, 572 F.2d 312, 197 USPQ 5 (CCPA 1978)). With regards to “reduction of disease progression is measured to be at least about 30% reduction relative to the rate of disease progression during the natural history of the patient,” Molinari discusses isotopically modified PUFAs such as deuterated PUFAs may reduce oxidation by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% [0073]. Additionally, the natural history of the patient refers to how an illness or condition progresses over time in an individual without any medical intervention or treatment (Centers for Disease Control and Prevention. Principles of epidemiology, 2nd ed. Atlanta: U.S. Department of Health and Human Services;1992). Therefore, reduction of disease progression that is measured to be at least about 30% reduction relative to the rate of disease progression during the natural history of the patient is inherently taught as a result of a reduction in oxidation following administration of PUFAs. The significant reduction in oxidation as taught by Molinari would necessarily result in at least 30% reduction in disease progression.
Regarding claim 2, Molinari specifically teaches the diseases Friedreich's ataxia [0037], Alzheimer's Disease [0037], and late onset Tay- Sachs [Abstract, 0019, 0038, 0162, claims 4, 5].
Regarding claim 3, Molinari specifically teaches that RBC concentration is used as a proxy for therapeutic concentration of deuterated arachidonic acid [0050, 0086].
Regarding claims 8-10, Molinari specifically teaches 7,7,10,10,13,13-D6-arachidonic acid ([0113], lines 8,9). Molinari specifically teaches deuterated arachidonic acid was observed as present in the plasma at 0.6% and 3.0% of total arachidonic acid [0050, 0159] and the 0.5% concentration is inherently taught as it is very close to the percentages taught by Molinari.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Applicant Claims
2. Determining the scope and contents of the prior art.
3. Ascertaining the differences between the prior art and the claims at issue, and 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 4 and 11-19 are rejected under 35 U.S.C. 103(a) as being unpatentable over Molinari et al. (“STABILIZED POLYUNSATURATED COMPOUNDS AND USES THEREOF”, Pub. No.: WO2019/204582A1; Pub. Date: Oct. 24, 2019) herein referred to as Molinari as evidenced by Alayash et al. “Hemoglobin Oxidation Reactions in Stored Blood.” Antioxidants (Basel, Switzerland) vol. 11,4 747. 8 Apr. 2022 and Centers for Disease Control and Prevention. Principles of epidemiology, 2nd ed. Atlanta: U.S. Department of Health and Human Services;1992
Regarding claim 4, Molinari teaches a method of claim 1 as discussed above. Molinari teaches the measurement of the efficacy of treatment by comparing the baseline amount of the fatty acid compared to after treatment for 30 and 120 days (para [0164], Table 1) and the monitoring of the efficacy of treatment (Fig 1 showing the monitoring of neuronal and motor functions over the period of treatment compared to a baseline).
Molinari does not specifically disclose wherein a percent reduction in the rate of disease progression is determined by: measuring a natural rate of disease progression in a patient or an average natural rate of disease progression in a cohort of patients; measuring the rate of disease progression in said patient or cohort of patients during a period of compliance with the administering step; and calculating the difference between the natural rate and the rate during the period of compliance, dividing the difference by the rate of disease progression during the natural history of the patient, and multiplying by 100.
It would have been obvious to a person having ordinary skill in the art to infer that such a monitoring can include wherein a percent reduction in the rate of disease progression is determined by: measuring a natural rate of disease progression in a patient or an average natural rate of disease progression in a cohort of patients; measuring the rate of disease progression in said patient or cohort of patients during a period of compliance with the administering step; and calculating the difference between the natural rate and the rate during the period of compliance, dividing the difference by the rate of disease progression during the natural history of the patient, and multiplying by 100; through routine experimentation. One would have been motivated to do so in order to evaluate periodic repeat assessments (including baseline measurement of PK, activities of daily living (ADL), in particular, ADLs were measured individually on a scale of 0-5 across a 12-element panel representing speech, strength, coordination, etc.), results ( for example 11,1l-D2-linoleic acid (D-LA) was elongated to 13,13-D2-arachidonic acid (D-AA) and both deuterated PUFAs achieve significant plasma levels and red blood cell (RBC) membrane incorporation within 1 month of administration. [0164]), and no major toxicities were seen (Table 1) as taught by Molinari.
Regarding claim 11, Molinari discloses a method for reducing disease progression (para [0159], clinical examination at 3 months showed no progression of disease since the start of the trial) of a neurodegenerative disease (para [0005]. Molinari specifically teaches 7,7,10,10,13,13-D6-arachidonic acid ([0113], lines 8,9) treating a subject having, or at risk for an infantile neuroaxonal dystrophy (IN AD) or PLA2G6 associated neurodegeneration) treatable with 7,7,10,10,13,13-D6-arachidonic acid or an ester thereof in an adult patient (para [0112], 7,7,10,10,13,13-D6-arachidonic acid), the method comprising: administering 7,7,10,10,13,13-D6-arachidonic acid or ester thereof to the patient (para [0004], comprising administering to the subject an effective amount of a substituted compound selected from a polyunsaturated fatty acid; and para [0112], disclosing the 7,7,10,10,13,13-D6-arachidonic acid or ester thereof ); wherein the dosage is administered over a period of time (para [0086], compound may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks or 8 weeks) and monitoring the plasma levels of the administered compound over the time period (para [0086], detecting the steady state plasma level of the substituted compound, or the level of the substituted compounds within red blood cell membrane to determine the incorporation level of the substituted compound.) wherein the dosage amount is from 0.1-20 g (para [0084], effective amount is 0.1-20 g) administered as a tablet (para [0084], form of four to five tablets) and monitoring the effect of the treatment (Figure 1 showing the monitoring of the efficacy of treatment), such that the rate of disease progression is reduced, wherein the neurodegenerative disease is mediated at least in part by lipid peroxidation of polyunsaturated fatty acids in neurons of the patient(para [0039], lipid peroxidation chain reaction is the target of the substituted compounds of the invention).
Molinari does not specifically disclose a dosing regimen that comprises a primer or loading dose and a maintenance dose thereby reducing said disease progression in said patient, wherein a) said primer or loading dose comprises periodic administration of from about 0.5 grams to about 5 grams of 7,7,10,10,13,13-D6-arachidonic acid or ester thereof per day, wherein said primer dose is continued for about 24 days to about 45 days; and b) subsequent to the completion of the primer or loading dose, administering said maintenance dose of about 30 to about 70 percent of the primer or loading dose of 7,7,10,10,13,13-D6-arachidonic acid or ester thereof per day thereof.
It would have been obvious to a person having ordinary skill in the art to infer from the disclosure of Molinari that the dosage regimen can be divided into a primary dosage and a maintenance dosage after the primary dosage; and monitoring the concentration and efficacy; through routine experimentation. The optimum amounts of the presently claimed primary dosage and a maintenance dosage would have been a matter well within the insight of one of ordinary skill in the art. Such a determination would have been made in accordance with a variety of factors, such as the route of administration, pharmacological considerations, such as the activity, efficacy, pharmacokinetics and toxicology profiles of the combination regimen, as well as the age, weight, sex, diet and medical condition of the patient, and the severity of the condition. Thus, the determination of the optimum or workable amounts given the guidance of the prior art would have been generally prima facie obvious to the ordinary skilled artisan. Please see MPEP 2144.05 [R-2] (II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (“[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation"). Accordingly, the particular dosage regimen that comprises a primer or loading dose and a maintenance dose claimed do not impart patentability to the claims, absent a showing of the criticality of the particular amounts claimed.
Regarding claim 12, Molinari discloses a method of claim 11 as discussed. Molinari further discloses monitoring the concentration of 7,7,10,10,13,13- D6 arachidonic acid in the patient to ensure that the patient maintains a therapeutic concentration of said 7,7,10,10,13,13- D6 arachidonic acid (para [0086], level of the substituted compounds within red blood cell membrane to determine the incorporation level of the substituted compound); and increasing the dosing of 10, 13-D6 arachidonic acid or an ester thereof when said concentrations of 7,7,10,10,13,13- D6 arachidonic acid are deemed to be less than a therapeutic concentration (para [0084]-[0086], disclosing the dosage and monitoring to adjust dosage to reach steady state plasma levels).
Regarding claim 13, Molinari discloses a method of claim 12 as discussed. Molinari further discloses which further comprises restricting the patient's consumption of excessive dietary polyunsaturated fatty acids during said primer or loading dose and said maintenance dose (para [0050], sustained feeding of a diet lacking LA).
Regarding claim 14, Molinari specifically teaches the diseases Friedreich's ataxia [0037], Alzheimer's Disease [0037], and late onset Tay- Sachs [Abstract, 0019, 0038, 0162, claims 4, 5].
Regarding claim 15, Molinari discloses a method of claim 11 as discussed. Molinari further discloses wherein the therapeutic concentration of 7,7,10,10,13,13- D6 arachidonic acid is determined by its concentration in red blood cells (para [0086], level of the substituted compounds within red blood cell membrane to determine the incorporation level of the substituted compound).
Regarding claim 16, Molinari discloses a method of claim 15 as discussed. Molinari specifically teaches that RBC concentration is used as a proxy for therapeutic concentration of deuterated arachidonic acid [0050, 0086]. Molinari discloses wherein the concentration is 1-60 percent (para [0109], patient maintains a sufficient concentration of the deuterated fatty acid and para [0144], effective amounts of isotopically modified PUFAs may be 1-60 percent).
Molinari does not specifically disclose wherein the concentration of 7,7, 0, 10, 13-D6- arachidonic acid in the red blood cells is at least about 0.5 percent based on the total number of fatty acids contained therein.
It would have been obvious to a person having ordinary skill in the art to substitute therapeutic concentration of deuterated arachidonic acid with that of 7,7, 0, 10, 13-D6- arachidonic acid. One of ordinary skilled in the art would have been motivated to do so to analyze tissue uptake and distribution which indicates that administration of substituted compounds (e.g., D-PUFA and ester thereof) and their derivatives are incorporated into tissues as taught by Molinari [0050].
Regarding claim 17, Molinari discloses a method of claim 11 as discussed. Molinari specifically teaches 7,7,10,10,13,13-D6-arachidonic acid ([0113], lines 8,9). Molinari teaches the amount of the substituted compound administered per day is from about lg to about 20g, the amount of 11,1 l-D2-linoleic acid or the ester thereof administered per day is from about 2 g to about 10 g. In another embodiment, the amount of 11,1 l-D2-linoleic acid or the ester thereof administered per day is from about 1.8 g to about 9g [0084].
Molinari further discloses wherein the dosage is administered over a period of time (para [0086], compound may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks or 8 weeks) and monitoring the plasma levels of the administered compound over the time period (para [0086], detecting the steady state plasma level of the substituted compound, or the level of the substituted compounds within red blood cell membrane to determine the incorporation level of the substituted compound.) wherein the dosage amount is from 0.1-20 g (para [0084], effective amount is 0.1-20 g) and monitoring the effect of the treatment (Figure 1 showing the monitoring of the efficacy of treatment), such that the rate of disease progression is reduced, wherein the neurodegenerative disease is mediated at least in part by lipid peroxidation of polyunsaturated fatty acids in neurons of the patient(para [0039], lipid peroxidation chain reaction is the target of the substituted compounds of the invention).
Molinari does not specifically disclose a dosing regimen that comprises a) administering said primer or loading dose to said patient at least about 0.5 grams of 1,11-D2-linoleic acid or an ester thereof wherein said first dosing component is continued for a period of from about 24 to about 45 days to provide a therapeutic concentration of 7,7,10,10,13,13-D6 arachidonic acid in red blood cells thereby reducing the rate of disease progression; and b) subsequent to the period of from about 24 to about 45 days of administering said primer or loading dose administering the maintenance dose to said patient, said maintenance dose comprising about at least 0.15 grams of 7,7,10,10,13,13-D6 arachidonic acid or an ester thereof to maintain a therapeutic concentration of 7,7,10,10,13,13-D6 arachidonic acid provided that said maintenance dose is less than said primer dose.
It would have been obvious to a person having ordinary skill in the art to optimize the dosage amounts as discussed above and infer from the disclosure of Molinari that the dosage regimen can be divided into a primary dosage and a secondary dosage after the primary dosage; and monitoring the concentration and efficacy through routine experimentation. One of ordinary skilled in the art would have been motivated to do so to better understand clinical study results, wherein the clear reversals indicate that substituted compounds are effective for treating a subject having, or at risk for, a disease or condition associated with an impaired Phospholipase A2 Group VI (PLA2G6) activity, and particularly the stabilized PUFA (11,1 l-D2-linoleic acid) [0161]. Example 2 explicitly demonstrates a case study of using 11 ,1 l-D2-linoleic acid ethyl ester to treat a single patient with late onset Tay- Sachs disease (LOTS) and the study results were reported; 11, l l-D2-linoleic acid ethyl ester was administered to the patient at 2.7 g (BID) and periodic repeat assessments including baseline measurement of PK, activities of daily living (ADL), 25 foot walk time (25FWT), and 6 minute walk distance (6MWD) were made. In particular, ADLs were measured individually on a scale of 0-5 across a 12-element panel representing speech, strength, coordination, etc. Results proved that 11, 11-D2-linoleic acid (D-LA) was elongated to 13,13-D2-arachidonic acid (D-AA) and both deuterated PUFAs achieve significant plasma levels and red blood cell (RBC) membrane incorporation within 1 month of administration. Improvements in ADL, 25FWT, and 6MWD have also been seen. No major toxicities have been seen (Table 1) as taught by Molinari [0164].
Regarding claim 18, Molinari discloses a method of claim 17 as discussed. Molinari further discloses monitoring the concentration of 7,7,10,10,13,13-D6 arachidonic acid in the patient to ensure that the patient maintains a therapeutic concentration of 7,7,10,10,13,13-D6 arachidonic acid(para [0086], level of the substituted compounds within red blood cell membrane to determine the incorporation level of the substituted compound); and increasing the dosing of 7,7,10,10,13,13-D6 arachidonic acid or an ester thereof when said concentrations of
7,7,10,10,13,13-D6 -arachidonic acid are deemed to be less than a therapeutic concentration (para [0084-0086], disclosing the dosage and monitoring to adjust dosage to reach steady state plasma levels).
Regarding claim 19, Molinari discloses a method of claim 18 as discussed. Molinari further discloses which further comprises restricting the patient's consumption of excessive dietary polyunsaturated fatty acids during said primer or loading dose and said maintenance dose (para [0050], sustained feeding of a diet lacking LA).
Free of Prior Art
With regards to the applicant’s elected species of deuterated arachidonic acid (7,7,10,10,13,13-D6-arachidonic acid) and neurodegenerative disease (amyotrophic lateral sclerosis - ALS), the examiner has determined that there is no prior art that is either anticipatory or rendered obvious of these two elected species.
Conclusion
Claims 1-4, and 8-19 are rejected.
No claims are allowed.
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/SAHAR INAM/
Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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