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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/30/2024 has been entered.
Election/Restrictions – Retained for the Record
Applicant’s election without traverse of Group I, claims 1-5 and 714 in the reply filed on 12/21/22 is acknowledged.
The following species elections also are acknowledged in the 12/21/22 reply:
With respect to the species requirements, Applicants select:
A. The peptide which consists of the sequence SEQ ID NO: 1;
B. Non-slow progression; and
C. Bolus injection, 2.5-4.5 mg/kg
Upon further consideration, and particularly in view of the interpretation of non-slow progression to include rapid progression, see claim interpretation section below, the claims examined for the elected species was broadened to include those directed to rapid progression.
Applicant stated it believed that claims 1, 2, 5, 7, 8, 9, 11-14 are readable on the elected species. Regarding claims 11-14, although only claim 11 appears explicitly directed to the elected species dosage of 2.5-4.5 mg/kg, given the overlaps in ranges all of claims 11-14 are under examination.
Claims 3 and 10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/21/22.
Claims 6, 15-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/21/22.
Claim Status
Claims 1-6, 10-12, 15-20 are pending.
Claims 7-9, 13, 14 are canceled.
Claims 3 and 10 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/21/22.
Claims 6, 15-20 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/21/22.
Claims 1, 2, 4, 5, and 11-12 are pending and under examination.
Claims 1, 2, 4, 5, and 11-12 are rejected.
Priority
The instant application, filed 11/26/2020 has two RCEs filed therein and is a Continuation in Part of PCT/IL2019/050619 , filed 05/30/2019
PCT/IL2019/050619 Claims Priority from Provisional Application 62678316, filed 05/31/2018.
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the3/3/24, 5/19/24, 5/26/24, 6/30/24, 9/1/24, 10/20/24, 1/1/25, 2/27/25, 3/12/25, 4/9/25 Information Disclosure Statements, and provides a signed and dated copy of each herewith.
Claim Interpretation
The claim limitations are given their broadest reasonable interpretation (BRI) consistent with the specification, MPEP 2111, and under the BRI, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification, MPEP 2111.01.
The dosage ranges of claims 1, 11 and 12 are interpreted to include the respective range end points because this is the ordinary and customary meaning and there is nothing inconsistent with this in the specification.
Based on the statements on page 12, lines 2-5 of the specification, “As used herein, the phrase “peptide comprising an amino acid sequence as set forth in SEQ ID NO: 1” refers to IPL344 (LPPLPYP, SEQ ID NO: 1, also known as Stressin-1) peptide (see International Patent Application Publication Nos: WO2006/021954 and WO2012/160563, the contents of which are fully incorporated herein by reference),” where claims 1 and 7 recite “an amino acid sequence as set forth in SEQ ID NO:1” this is interpreted to only refer to and encompass the full seven residue amino acid sequence of SEQ ID NO:1, and to not include any shorter subsequence. MPEP 2173.05(a) III, states in part, “Consistent with the well-established axiom in patent law that a patentee or applicant is free to be his or her own lexicographer, a patentee or applicant may use terms in a manner contrary to or inconsistent with one or more of their ordinary meanings if the written description clearly redefines the terms.” Here the use of “an” before “amino acid sequence” does not indicate inclusion of any of a number of smaller peptides of SEQ ID NO:1, because per the applicant’s clear redefining the entire phrase only refers to and defines the entire seven amino acid residue peptide of SEQ ID NO:1.
Based on the statements on page 8, lines 13-16 of the specification, “As used herein, the phrase “non-slow progression ALS” refers to ALS with subject survival of up to 5 years from diagnosis. According to specific embodiments, the non-slow progression ALS is characterized by a change of above 0.55 ALSFRS-R points over a period of 1 month,” the latter sentence directed to specific embodiments rather than a definition, “non-slow progression” is interpreted as a phase or prognosis characterization of ALS in which the subject is expected, by a physician trained in ALS diagnosis and therapies, to survive up to 5 years starting at the time of first diagnosis. The examiner notes that this definition, as currently understood based on the above, encompasses rapid progression, which the specification at para 77 states, “As used herein, the phrase “rapid progression ALS” refers to ALS in which the symptoms progress continuously and significant degradation of motor neurons can be observed within less than a year with subject survival of up to 4 years from diagnosis.”
Claim 2’s “ALS Functional Rating Scale (ALSFRS)” is interpreted to include both ALSFRS and the revised form, designated ALSFRS-R, see para 87.
Claim 7’s “5% peptide” is interpreted as a weight volume measurement, that is 5 grams/100 milliliters, because this is the ordinary and customary use of this term for solid solutes. This also is consistent with applicant’s Example 1, para 243.
“About” per para 230 refers to +/- 10%.
Claim Rejections - 35 USC § 112
Response to Arguments
Applicant’s arguments, see page 4, filed 12/30/24, and claim amendments, with respect to the rejection of Claims 1, 2, 4, 5, and 11-12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite have been fully considered and are persuasive. The rejection of Claims 1, 2, 4, 5, and 11-12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite has been withdrawn.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 4, 5, and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over US 20160033529, Ovadia et al, published 2/4/16 (Ovadia, previously cited), in view of Usach et al., Adv Ther (2019) 36:2986–2996 (Usach, previously cited) and WO 2006/046109, published 5/4/2006 (JAD, previously cited), Grasela et al., Summary from Comprehensive Medicinal Chemistry III, 2017, summary from pages 51-82, 2 pages (GB, previously cited), US 2003/0140362, Macejak and Lee, published 7/24/2003 (ML, previously cited), and Doyle, Clinical Procedures for Safer Patient Care, 2015, CampusOpenEd, chapter 7.5 (Doyle, previously cited), as evidenced by Simon et al., ANN NEUROL 2014;76:643–657 (Simon, previously provided), blog downloaded 5/13/23 from https://www.als.net/news/50-years-with-als-what-can-we-learn-from-slow-progressors-like-stephen-hawking/, 2023 (ALSNETblog, previously provided), ThermoFisher Balanced Salt Solutions screen shot, taken from the internet 9/18/23 (TF, previously provided).
Claim 1 is directed to a method of treating amyotrophic lateral sclerosis (ALS) in a human subject in need thereof, the method comprising intravenously (IV) administering, on a daily basis, to the subject 2 - 5 mg / kg of a peptide consisting of an amino acid sequence as set forth in SEQ [D NO: 1, wherein the peptide is formulated in Dulbecco’s phosphate buffered saline (DPBS) at a concentration of 50 mg/ml, said DPBS comprising calcium and magnesium, wherein said administering is by bolus injection, thereby treating the ALS in the subject.
The elected species are the peptide which consists of the sequence SEQ ID NO: 1, so the exact peptide sequence Leu Pro Pro Leu Pro Tyr Pro, without additions or deletions or substitutions, non-slow progression, and bolus injection, 2.5-4.5 mg/kg.
Ovadia teaches treating ALS by administering its SEQ ID NO:1, Abstract, para 25, which is identical with instant SEQ ID NO:1: Leu Pro Pro Leu Pro Tyr Pro. Ovadia repeatedly teaches administering this peptide to treat ALS, including citing its advantages over other treatments, para 29, that it is safe based on testing in mice, so is suitable for chronic use, para 30, and also extensively teaches the discovery of its effect on the Akt pathway, and how the ratio of pAkt:tAkt can be used for staging and monitoring the progression of ALS, para 31. Para 36 states, “According to an aspect of some embodiments of the present invention there is provided a method for treating amyotrophic lateral sclerosis (ALS) in a subject in need thereof, comprising (a) assessing the level of pAkt and pAkt:tAkt ratio in bodily sample derived from the subject; and (b) administering a therapeutically effective amount of a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2 and an analog or a derivative thereof, to a subject having pAkt level or pAkt:tAkt ratio significantly below a control value.”
Although Ovadia’s method involves more steps, clearly Ovadia teaches administering SEQ ID NO:1 to treat ALS; closely related Ovadia teaches the use of measuring the level of pAkt and pAkt:tAkt ratio in determining what subject(s) to treat, and also the effectiveness of the treatment.
The latter is made even clearer in para 37, “According to an aspect of some embodiments of the present invention there is provided a method for assessing responsiveness to treatment of a disease with a peptide comprising an amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2 or an analog or a derivative thereof, or a pharmaceutical composition comprising same, the method comprising: assessing the level of pAkt or pAkt:tAkt ratio in bodily sample derived from a subject, wherein responsiveness to treatment is indicated by a pAkt level or pAkt:tAkt ratio significantly above a value of a pAkt level or pAkt:tAkt ratio in the subject prior to the treatment.” Given the knowledge and level of skill in the art, this suggests modifying the amount of SEQ ID NO:1 or SEQ ID NO:2 peptide to administer depending on measurements of pAkt or pAkt:tAkt ratio in bodily sample derived from a subject, taken over time during such administering.
Ovadia teaches that its use of the term ALS “includes sporadic and familial ALS, ALS at any rate of progression (i.e. rapid or slow progression) and ALS at any stage (e.g. prior to onset, at onset and late stages of ALS),” para 79, so is fully inclusive of applicant’s elected non-slow progression, which, per claim interpretation above, also encompasses fast progression.
Ovadia teaches formulation of its compounds in aqueous solutions, preferably in physiologically compatible buffers, listing among such physiological saline buffer, para 113.
The level of ordinary skill in the art is high, including highly educated researchers and physicians specializing in neurodegenerative disorders and diseases.
To one of ordinary skill in the art, based on this statement from Ovadia indicating “at any stage” it would be apparent that Ovadia intends to include all progressions, including what applicant has stated as “non-slow.” Therefore treating non-slow progressing ALS with the peptide consisting of instant SEQ ID NO: 1 would have been obvious.
Ovadia teaches bolus injection among other known forms of administering a therapeutic agent, page 109, but does not teach the claim 1 claimed dosage range nor the somewhat narrower elected species dosage range.
However, Ovadia teaches “Although an appropriate dosage of a peptide of the invention varies depending on the administration route, age, body weight, sex or conditions of the patient, and should be determined by the physician in the end, the dose suitable for adult humans can generally be between about …” and then recites multiple ranges of dosages including about 1-100 mg/kg body weight, para 123. Given the teachings above regarding measuring pAkt or pAkt:tAkt ratio in bodily sample derived from a subject, as indicated above, a proper effective dosage within such range would be developed.
MPEP 2144.05 I begins, “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).” MPEP 2144.05 II.A. begins, “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Ovadia’s 1-100 mg/kg body weight dosage range encompasses the narrower claim 1 claimed range of 2-5 mg/kg, and the elected species range of 2.5-4.5 mg/kg, and also the ranges (including the “about” ranges of claims 13 and 14) of dependent claims 12-14 as reasonably understood. The examiner has not identified any criticality of any of these ranges, and Ovadia’s cited teaching that appropriate dosages are subject to many factors and are left to the determination of the physician, leads the examiner to conclude that it would have been routine optimization to arrive at the claimed and species-elected ranges. A person of ordinary skill in the art understanding the teachings of Ovadia would have had a reasonable expectation of success to formulate the claimed range and the narrower elected species range and to administer the peptide within these ranges and achieve at least some level of treatment effectiveness at least for some patients having ALS, particularly given the known variability of ALS, as evidenced by Simon, broadly discussing heterogeneity in ALS, and additionally by ALSNETblog, which specifically points to ALS heterogeneity stating on its first page “no two cases are like” and “the fact that ALS is, in actuality, more like a syndrome than a disease – a set of symptoms that can be related to different causes from case to case.”
Assuming, arguendo, that the upper area of the range toward and including 100 mg/kg body weight dosage of this range of Ovadia would give too many undesired adverse effects or be beyond a therapeutically effective dosage, this would reasonably have been determined, again, by routine optimization, including the teachings of GB as to pharmacodynamics, particularly, “The target concentration range is the range of plasma drug concentrations defined by the minimum effective concentration and the maximum therapeutic concentration. Dosing regimens that deliver concentrations below the minimum effective concentration may not provide an adequate therapeutic response. Conversely, regimens that deliver concentrations above the maximum therapeutic concentration may result in adverse events,” page 1, and Fig. 1 on page 2. One of ordinary skill in the art would recognize this targeting of dosage when moving from rodent or other test animal data with SEQ ID NO:1 to evaluations with human subjects, and reasonably would have determined suitable dosage ranges. This would further influence what part(s) of the Ovadia dosage range to further evaluate for effectiveness in treating ALS. Again, this would be routine in the art to determine an effective dose that balances the effectiveness against undesired effects including side effects that would result in cessation of the therapy.
One of examiner’s points in referencing GB is that getting to a safe and therapeutic dose range is well understood by those skilled in the art, and also given that ALS is variable among afflicted subjects, see above, a somewhat wider range might be considered initially, below the level of adverse effects shown in GB Figure 1, toward evaluating tolerability and effectiveness in a range of ALS subjects, and with sufficient evaluations the dosage range further narrowed based on results. Ongoing evaluations over time, such as including by measuring pAkt or pAkt:tAkt ratio in bodily sample derived from a subject, would have been reasonably envisioned.
This further supports that the claimed dosage ranges would have been obvious based on routine optimization.
Ovadia teaches administering the same peptide as instant SEQ ID NO:1 on a daily basis, para 30, Table 1 below para 194, paras 197, 202, 203, so this would have been an obvious approach when treating human subjects.
Ovadia teaches administering the same peptide as instant SEQ ID NO:1 to mice in amounts of 200 ug IV and 200 ug IP (intraperitoneal), compared to controls that either were untreated or treated with PBS (this by inference indicating that the injected SEQ ID NO:1 peptide also was prepared in PBS – if not, why compare to this?), paras 70, 71, Tables 1 and 2 below para 194, para 198. Ovadia does not teach what volume comprised the 200 ug (although this would be known to applicant, being a co-inventor of Ovadia). Although Ovadia teaches administering PBS as one of the controls, this inferring that the SEQ ID NO:1 peptide was in PBS when administered, Ovadia does not explicitly teach “wherein the peptide is formulated in Dulbecco’s phosphate buffered saline (DPBS) at a concentration of 50 mg/ml.”
As to this claimed concentration, MPEP 2144.05 II A states that, “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” It would have been routine optimization to arrive at the claimed invention concentration, 50 mg/ml, because solubility of the peptide is an inherent property and obtaining this solubility at this desired concentration would have been the result of routine evaluation of solvents, and given the use of PBS already taught by Ovadia using this solvent or modifying it would have been an obvious approach. The objective of increasing concentration to reduce injection volume would have been understood by a person of ordinary skill in the art, at least based on Doyle, page 1, which teaches that “The direct IV route usually administers a small volume of fluid/medicine (max 20 ml) that is pushed manually into the patient,” and a person of ordinary skill in the art would have had a reasonable expectation of success to formulate the claimed concentration given predictable properties of peptides based on their respective amino acid sequences.
Further, Usach focusing on subcutaneous administration route teaches that ideally injectable products should be formulated as isotonic solutions, about 300 mOsm/kg and no more than 600 mOsm/kg, at a pH close to physiological pH, and “Buffers are frequently added to parenteral formulations to optimize solubility and stability by adjusting the pH; however, their strength should be kept as low as possible to avoid pain upon injection. The data available recommend the concentration of phosphate buffer be limited to 10 mM and that the concentration of citrate buffer should be lower than 7.3 mM to avoid an increased sensation of pain,” page 2986.
More specifically regarding Dulbecco’s PBS, JAD teaches use of Dulbecco’s PBS solution for dissolving its therapeutic agent atorvastatin, page 8 lines 20-26, and in an example specifically dissolves its therapeutic agent in Dulbecco’s PBS when preparing it for lyophilization, page 10, Example 2. This suggests the general usefulness and acceptability of DPBS as a buffer solution for therapeutic agents. Additionally, the evidentiary reference TF teaches that both phosphate buffered saline (PBS) and Dulbecco’s PBS “are common reagents used in biological research to maintain pH while minimizing osmotic shock in living cells.” TF additionally teaches that Dulbecco’s PBS “may be formulated with or without calcium and magnesium … based on your specific application.”
Further regarding the added limitation that “said DPBS comprising calcium and magnesium,” ML teaches that it injected cells into a mouse that were suspended in Dulbecco's PBS solution including calcium and magnesium, para 36, thus suggesting that this particular Dulbecco PBS formulation was suitable for injecting into a subject. Dulbecco’s PBS with calcium and magnesium is one of only several commercially available formulations from which to choose, and ML provides a motivation to choose this based on its use for an injection. There would have been a reasonable expectation of success with this formulation given its use in ML.
Given Ovadia’s clear teaching of administering SEQ ID NO:1 to treat ALS, its dosage range encompassing the claimed ranges and the latter per above reasonably obtainable by routine optimization, this further supported by the teachings of Doyle, the clearly stated knowledge in the art per Usach of the importance of formulated as isotonic solutions, at a pH close to physiological pH, and that PBS as well as DPBS are common buffer solutions that achieve these objectives, with ML providing a suggestion to use a DPBS formulation with calcium and magnesium for injection into a subject, one of ordinary skill in the art would have routinely selected DPBS with calcium and magnesium when formulating a therapeutic agent formulation for administering SEQ ID NO:1 to treat ALS. There would have been a reasonable expectation of success based on the rodent results of Ovadia, the teachings regarding osmotic and pH recommendations per Usach, and the specific teaching of injecting into a subject with Dulbecco’s PBS with calcium and magnesium per ML.
There remains insufficient evidence of an unexpected or surprising result, long felt need or other secondary consideration consistent with and commensurate with what is claimed.
Accordingly, claim 1 would have been obvious.
Because Ovadia teaches administering compositions its peptide including SEQ ID NO:1 to treat ALS, para 72 and elsewhere, and that it considers ALS at any rate of progression (i.e. rapid or slow progression), para 79, and per the instant claim interpretation above “non-slow progression of ALS” includes rapid progression, so that Ovadia’s treatment of rapid progression ALS is treating a species/subgenus of the claimed non-slow progression of ALS, claims 4 and 5 would have been obvious.
Claim 11, interpreted under this section to mean that the claim 1 dosage range of 2-5 mg/kg is narrowed to the elected dosage range, 2.5-4.5 mg/kg body weight of the subject, is rejected on the same basis as claim 1 above.
Claim 12, interpreted under this section to mean that the claim 1 dosage range of 2-5 mg/kg is narrowed to the dosage range of 3-4 mg/kg body weight of the subject, also is rejected on the same basis as set forth for claim 1.
That is, it would have been routine optimization to narrow the dosage to a dosage range that was found to be particularly effective. (Conversely, the examiner also is of the opinion that given that ALS is variable among afflicted subjects, see Simon and ALSNETblog above, the relatively narrow claim ranges may provide sub-optimal dosages for some subjects.)
Response to Arguments and Declarations
Applicant's arguments filed 12/30/24, and the Declaration also filed 12/30/24, and the arguments particularly regarding long felt unmet need, have been fully considered but they are not persuasive. Also considered is the previously considered Declaration filed 9/4/23.
Applicant on page 5 of the 12/30/24 Remarks (and elsewhere) asserts “that identification of a regimen for treatment of ALS answers a long-felt and unmet need, which the currently claimed regimen satisfies.”
The examiner has consider this, all related arguments, assertions and data, and responds with the following analysis.
However, before this analysis the examiner notes that on page 2 of the Declaration filed 12/30/24 Dr. Cohen states, “Results presented in the attached appendix testify to the efficacy of the claimed peptide at the claimed regimen.” The examiner searched and did not find results of applicant, rather the examiner found Dr. Cohen’s CV and a lengthy Withdrawal Assessment report for Radicava from the European Medicines Agency. As memorialized by the attached Interview Summary, the examiner left two messages inquiring about these results, and no answer was received. Due to no response and no data or other information identified in the submissions of 12/30/24 that corresponds with Dr. Cohen’s reference to results, little weight can be given to this assertion of results in an appendix because no accompanying results or data was found.
As to considering Dr. Cohen’s Declaration, given that the examiner could not find the referred-to results in the appendix, the examiner reasonably is not persuaded by Dr. Cohen’s opinion that “these results are unprecedented as other drugs which are known to be effective for treating ALS (such as Riluzole and Erdavone), do not both enhance weight gain and decrease neurofilament concentrations.” The examiner does not understand whether “The Appendix demonstrate the stringent analyses carried out in order to obtain statistically significant results” refers to the analyses carried out by the European Medicines Agency regarding Radicava, new data not provided, or the data found in the specification. If the latter, the examiner is not persuaded given that the asserted statistically significant results are not shown for biomarker data, see page 40, and
The analysis and weighing of evidence for long felt but unmet need is addressed first:
Per MPEP 716.04, establishing that the claimed invention satisfies a long-felt but unmet need requires:
the need must have been a persistent one that was recognized by those of ordinary skill in the art;
The examiner does not dispute that ALS is a very serious medical condition for which neither a cure nor a highly effective treatment therapy that substantially delayed (or even reversed) disease progression for all stages of disease or extended lifetime has been found. Applicant’s assertion of long-felt unmet need focuses on identification of a regimen for treatment of ALS, so cure is not at issue.
the long-felt need must not have been satisfied by another before the invention by the inventor;
There are a few approved medicines for treating ALS, such as Riluzole and Edaravone (aka Radicava). Applicant states that it traverses the fact that these are known treatments by disputing the effectiveness of these prior art treatments, including the withdrawal of approval for Radicava (Withdrawal assessment report is a significant portion of the12/30/24 Declaration attachments).
Relevant to many of applicant’s arguments and of data that is found in the application and that is argued in comparisons, the following is from the referenced Radicava Withdrawal assessment report:
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This excerpt is provided to set forth a number of considerations and factors that were considered for Radicava and its withdrawal.
The fact remains that in other jurisdictions both Riluzole and Edaravone (aka Radicava), and a newer entrant, tofersen, are approved and administered to ALS patients, with a range of results, see ALS Therapy Development Institute, downloaded from the worldwide web, 2025, 8 pages (ALSTDI). While Applicant points to tolerance, dosing and other issues with Riluzole, two pivotal trials involving over 1000 patients were conducted, and per ALSTDI “a 202 publication evaluating real world evidence of Riluzole’s effectiveness indicated a median survival benefit for people taking riluzole could range from 6 to 19 months,” page 2. Also, tofersen was stated to be approved for use by people with SOD1 ALS based on reductions in levels of neurofilament light chain, page 3. This teaches another compound that may be effective for a subgroup of ALS patients, and again points to variability among ALS subjects.
Please also observe that a short article in The Harvard Gazette, entitled High-calorie feeding may slow progression of ALS,” author Sue McGreevey, 2/27/14, 4 pages, begins with the statement, “Increasing the number of calories consumed by patients with amyotrophic lateral sclerosis (ALS) may be a relatively simple way of extending their survival,” following at the end of the paragraph with the precautionary, “While the results need to be interpreted with caution because of the small size of the trial, the authors are optimistic that improved nutrition could make a significant difference for patients of ALS.”
At the present time, with the information at hand, the examiner concludes that there are treatments that delay progression of ALS, and dietary regimens that offer the chance of maintaining or gaining weight for at least some ALS patients.
-
and
the invention must in fact satisfy the long-felt need.
Applicant argues for differences from its ‘control’ (or “established surrogate for a placebo group), page 39 of specification, and rests the asserted differences on eight patients who “have completed a 28 days safety trial with IPL344,” first sentence of Example 3, page 39 of specification. Given the recognized variability among ALS patients, this is hardly a sufficient number of patients, nor a sufficient duration of treatment, in the examiner’s opinion, to establish that the claimed treatment regimen has met a long-felt but unmet need (given the available treatments, “unmet need” is here interpreted to provide a treatment of ALS that attains a delay or reversal at least twice as beneficial as known treatments across relevant patient stages of disease). Given the known “significant inter-patient variability” – acknowledged by Applicant when discussing Riluzule data, page 6 of Remarks, such variability not rationally diminished by virtue of treatment with Applicant’s peptide, the assertions regarding Applicant having satisfied a long-felt and unmet need with its regimen for treatment of ALS, after considering the data of 8 subjects1 and such known variability, are found to not have sufficient statistically significant and relevant support.
Applicant may consider providing more substantial data.
Applicant, page 7 of 12/30/24 Remarks, also briefly asserts unexpected results. Again, the study size constrains generalizability of this data, and the data as presented provokes more questions than it answers. The examiner does not fully understand what is being compared when contrasting IPL344 survival of 43.4 months, with 19.1 months “in the placebo group of ceftriaxone study”. Are these two different studies? And what numbers of patients per group, and what was the adjusted survival, and on what basis were adjustments made?
The following are retained with slight modifications from the previous response to Applicant’s arguments:
With regard to applicant’s arguments, page 5, that as to applicant providing evidence of unexpected effect in relation to other dose ranges, “it is unrealistic for the Examiner to expect comparative clinical data to show an inventive step. ALS is a rare, severely debilitating and ultimately fatal condition and it is not feasible to carry out such expansive studies, since comparative of the dose would require clinical experimentation on humans.”
While the examiner appreciates the stated difficulties, the MPEP at 716.02(d) II states, “To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960).” See also MPEP 716.02(b) in its entirety; this begins, “The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” The evidence offered in the (previous) Declaration, and also the specification, indicates a variability in outcomes that would be expected in view of the art, at least based on the teachings set forth above by the Simon and the ALSNETblog evidentiary references, and does not provide sufficient support to indicate unexpected results over what would have reasonably been expected when considering Ovadia’s clear teaching of administering the same peptide to treat ALS. As to dose comparisons, there are no other doses to compare with.
As to alleged long-felt need, applicant’s arguments are not sufficient to establish this, please see MPEP 716.02(c) and 716.04. With regard to the “enclosed review article,” made of record in and attached to this Office Action, Cell, 2023, 12 1523, 33 pages, the examiner observes that “real-world analyses suggest a higher survival benefit, ranging up to 19 months” for Riluzole, page 3, and for Edaravone “Results from the second Phase III trial were a 33% reduction of ALSFS-R decline over the 24-week treatment period and significantly better scoring on the ALSAQ-40 …”, Id. This provides evidence to counter applicant’s assertion that “the long-felt need has not been satisfied by others” first, because the latter 33% reduction is roughly comparable to applicant’s results with far fewer subjects, and second, the examiner notes that applicant still refers to its method as being to treat (“identification of a regimen for treatment of ALS answers a long-felt need”, page 5 of Remarks of 12/27/23), so the claimed method is to treat, as are the other therapeutic agents of this article, rather than to cure (which would be more toward a long-felt need, but which would need to be established by proper evidence).
The responses regarding the establishment of a time frame is set forth in the rejections above, and providing this time frame does not overcome the obviousness rejection as modified herein.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over US 20160033529, Ovadia et al, published 2/4/16 (Ovadia, previously cited), in view of Usach et al., Adv Ther (2019) 36:2986–2996 (Usach, previously provided) and WO 2006/046109, published 5/4/2006 (JAD, previously provided), Grasela et al., Summary from Comprehensive Medicinal Chemistry III, 2017, summary from pages 51-82, 2 pages (GB), US 2003/0140362, Macejak and Lee, published 7/24/2003 (ML), and Doyle, Clinical Procedures for Safer Patient Care, 2015, CampusOpenEd, chapter 7.5 (Doyle), as evidenced by Simon et al., ANN NEUROL 2014;76:643–657 (Simon, previously provided ), blog downloaded 5/13/23 from https://www.als.net/news/50-years-with-als-what-can-we-learn-from-slow-progressors-like-stephen-hawking/, 2023 (ALSNETblog, previously provided) and ThermoFisher Balanced Salt Solutions screen shot, taken from the internet 9/18/23 (TF), as applied to claim 1, further in view of WO 2016/077687, Sah et al., published 5/19/2016 (Sah, previously applied, provided in 12/18/22 IDS so copy not supplied).
The rejection of claim 1 is set forth above.
Claim 2 depends from claim 1 and states that claim 1 method comprises further monitoring the subject following the treatment by a short list including ALSFRS. Although Ovadia teaches the use of Akt phosphorylation and pAkt:tAkt ratio as biomarkers, stating that these are significantly useful for staging and monitoring the progression of ALS, para 31, and also teaches monitoring progression of disease symptoms by weight and neurological disability score, paras 201 and 203, monitoring by ALSFRS is considered an improvement over Ovadia because Ovadia does not explicitly teach monitoring by ALSFRS.
Sah teaches administering a different type of therapeutic agent, small interfering RNA molecules and AAV vectors encoding these to treat ALS, Abstract. Sah teaches that in one embodiment a therapeutically effective amount of the AAV vector is determined using a known evaluation method such as the ALS functional rating case (ALSFRS), para 228 on page 46. Sah thus teaches a method that has been improved in the same way as claim 2 as interpreted under this section (to monitor to determine an effective therapeutic dosage).
One of ordinary skill in the art knowing of the teachings of Ovadia and also Sah, wanting to treat a subject having been diagnosed with ALS with the SEQ ID NO:1 peptide of Ovadia, would have been motivated to find the appropriate dosage regimen for effective treatment for such subject, and would have considered monitoring the subject for improvement or deterioration of condition using ALSFRS following the peptide’s first administering based on Sah’s teaching of determination of a therapeutically effective amount using ALSFRS for determining its therapeutic agent’s therapeutically effective amount also for ALS. Sah’s use of ALSFRS improved its method in the same way as instant claim 2 would improve the instant claim 1 administering if done subsequent to the first administering toward refinement of the dosage regimen. The rationale is use of known technique to improve similar methods in the same way, see MPEP 2143.
Accordingly, claim 2 would have been obvious.
Response to Arguments
Applicant's arguments filed 12/30/24, and Declarations, have been fully considered but they are not persuasive.
Applicant, pages 4-6, appears to rely on the arguments and amendments of claim 1 to overcome the rejection of claim 2. The rebuttal provided above is incorporated and applied to find those arguments applied against claim 2 unpersuasive.
Conclusion
No claim is allowed.
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/JOSEPH FISCHER/Examiner, Art Unit 1658
1 Or six subjects, stated in Dr. Cohen’s Declaration entered 9/4/23, page 2. Or perhaps there was a total of 14 subjects; this is not clear from what has been provided. Further regarding this Declaration and the data presented, first, this is a very low number of subjects, second, FIG. 2A does show improvement relative to control, however this is not compared to known treatments’ effectiveness, nor is it established that the pre-treatment slope of FIG. 2B is following an accepted model (see above about comparison to “the placebo group of ceftriaxone study”). Please also not that the characters in FIG. 1 are indistinguishable, so no conclusion can be reasonably ascertained.