Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 of RCE on September 8, 2026 and amendment after final filed on September 8, 2026 has been entered. Claims 2-3, 6, 11-33 were canceled, claims 1, 4-5 were amended and claims 1, 4-5, 7-10 are pending in the instant application.
The restriction requirement was deemed proper and made FINAL in a previous office action. Claims 1, 4-5, 7-10 are examined on the merits of this office action.
Withdrawn Objections
The objection to claim 1 is hereby withdrawn in view of amendment of the claims filed September 8, 2026.
The rejection of claim(s) 1, 4-5, 7-11 under 35 U.S.C. 103 as being unpatentable over Haramizu (WO2013058229, English translation attached, cited previously) in view of Miyoshi (EMBO Mol Med, 2017 May 10;9(7):880–889, cited previously) is hereby withdrawn in view of amendment of the claims filed September 8, 2026.
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New Rejections
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.
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.
Claim(s) 1, 4-5, 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Haramizu (WO2013058229, English translation attached, cited previously) in view of Miyoshi (EMBO Mol Med, 2017 May 10;9(7):880–889, cited previously) and Arimura (Science, 19 SEPTEMBER 2014 • VOL 345 ISSUE 6203 1505-1510).
Haramizu teaches a method for treating an age related dysfunction in a human subject by administering a therapeutically effective amount of an NMJ targeting agent (see claims 1-9, 15-18). Specifically, Haramizu teaches that aging leads to skeletal muscle atrophy, weakness and decline in NMJ integrity and the administration of milk fat globule membrane component increases skeletal muscle mass, suppresses muscle atrophy and promotes NJM formation (see Examples 1-3, figures 1-5, Example 3 is specifically treating aged mice with fat globule membrane component and also claims 15-18). Haramizu specifically teaches “when the fat globule membrane component was administered to aging-promoted mice, gene expression or protein decrease of molecules (Dok-7) involved in the formation of the neuromuscular junction was suppressed”(see page 3 of translation, bottom of paragraph 0003).
Haramizu teaches administration of the MGFM composition to elderly subjects such as aged individuals with muscle weakness or reduced strength due to normal aging (see claims 18-19, “suppresses muscle atrophy associated with aging”, “NMJ dysgenesis associated with aging” (claim 19), “age related muscle weakness (sarcopenia)” (see page 3, paragraph 005)). The disclosure encompasses treatment of normal, age related NMJ function via treating age related weakness such as sarcopenia.
Haramizu is silent to using a polynucleotide encoding Dok-7 as the NMJ targeting agent or NMJ formation promoter.
However, Miyoshi teaches administration of AAV vector encoding DOK7 and that treatment restored NMJ integrity, suppressed atrophy and improved motor function (see page 881, Abstract and intro; Figure 1 (E-G)(NMJ restoration); Figure 2 (A-E)(myofiber CSA increase); figure 3 (F-G)(motor activity). Miyoshi explicitly teaches an AAV vector encoding human Dok-7 (see methods section, page 886, left column, “in vivo AAV injection”). Miyoshi demonstrates enhanced motor activity (figure 3 (F-G)). Miyoshi teaches AAV-DOK7 suppressed NMJ denervation and maintained nerve terminal contacts (see Figure 1E-G, text page 887, “the paper explained, results”). Miyoshi teaches that NMJ morphology and muscle strength are restored to levels greater than those of healthy controls (Figures 1E-G). Taken together, Miyoshi demonstrates that increasing Dok-7 expression restores NMJ structure and improves motor function.
Arimura further teaches administration of an AAV- human Dok 7 gene and demonstrates that forced expression of doc seven in skeletal muscle enhances activation of muscle-specific kinase and subsequent NMJ formation (see abstract, right column, page 1506, Figure 1). Arimura reports that AAV-DoK7 treatment promotes Musk mediated NMJ formation and results in stable enlargement of NMJs (see page 1505, Abstract, page 1506, Figure 1). Arimura Demonstrates this effect in wild type mice rather than only an animal suffering from a neuromuscular disease. Specifically Arimura reports that one week after AAV-Dok7 injection, NMJS work clearly enlarged in the central region of the diaphragm muscle of treated wild type mice and concludes that treatment promotes Musk mediated formation of NMJs (see page 1506, left column, figures 1A-D, Figure 1 legend). Arimura provides additional evidence that the NMJ promoting effect of increased Dok7 expression is not dependent upon the presence of ALS or another disease specific pathology because AAV DoK7 itself promotes NMJ formation enlargement in wild type animals (see figure 1). Arimura teaches that Dok7 therapy may be applicable to other neuromuscular disorders associated with abnormalities of NMJ structure but not caused by DOK7 mutations.
It would have been obvious before the effective filing date of the claimed invention to one of ordinary skill in the art to administer a polynucleotide encoding human DOK-7, as taught by Miyoshi, to subjects experiencing age related motor impairment (including muscle atrophy and sarcopenia) as taught by Haramizu. Arimura Provides further reason for one of ordinary school in the art to make this combination because Arimura teaches that increasing DoK7 expression promotes Musk mediated NMJ formation and enlargement and expressly teaches applicability of DoK7 therapy beyond a single disease model. One of ordinary skill in the art would have been motivated to do so because Haramizu teaches that aging is associated with skeletal muscle atrophy, weakness, and decline in NMJ integrity/function, and further teaches that reduced expression or activity of molecules involved in NMJ formation, including DOK-7, contributes to age related NMJ dysfunction. Miyoshi teaches that increasing Dok-7 expression via administration of an AAV vector encoding human DOK7 restores NMJ integrity, suppresses NMJ denervation, reduces muscle atrophy and improves motor function in vivo.
Arimura Further supports this motivation by demonstrating that increased Dok7 expression itself promotes Musk mediated NMJ formation and produces enlargement of NMJs, including in wild type animals. Arimura provides evidence that Dok7 mediated enhancement of NMJ structure is not merely an effect of specific to treatment of ALS.
Accordingly, Haramizu identifies Dok-7 signaling as a contributing factor in age related motor impairment, and Miyoshi demonstrates that restoring Dok-7 expression improves NMJ structure and motor performance, one of ordinary skill in the art would have had a reasonable expectation that increasing Dok-7 expression in aged subjects would restore NMJ integrity and improves muscle strength.
This reasonable expectation is further supported by Arimura’s demonstration that AAV mediated Dok7 expression promotes Musk mediated NMJ formation and stable NMJ enlargement across different experimental contexts including wild type mice.
Regarding claim 1, Haramizu teaches treatment of age related muscle atrophy and sarcopenia with MFGM administration (see page 4, paragraphs 1-2, “age related muscle weakness (sarcopenia)”) thus meeting the limitations without MG, ALS etc.. as claimed in instant claim 1. Regarding treatment of human subjects who are 60 years or older, Haramizu does not expressly recite treatment limited to humans that are 60 years or older. However, Haramizu does teach that “Our skeletal muscles decrease at a rate of about 5% every 10 years after the age of 30, and the rate of reduction further accelerates after the age of 60” (see paragraph 3). Haramizu further teaches that “decrease in skeletal muscle mass and muscle function associated with aging causes injury due to falls, resulting in a decrease in physical activity, and accordingly increases the risk of metabolic disorders such as osteoporosis, obesity and insulin resistance” (see paragraph 0003). Thus, Haramizu recognizes that age 60 and older as a clinically significant stage of age related skeletal muscle decline and associated motor impairment. Accordingly, one of ordinary skill in the art would have understood that treatment of age related motor impairment as taught by Haramizu would reasonably encompass subjects 60 years or older, as this age group is specifically identified as experiencing accelerated skeletal muscle degeneration. Selecting human subjects 60 years or older for treatment of age related motor impairment would have been obvious because Haramizu identifies 60 as stage of accelerated skeletal muscle decline.
Regarding claims 1, 4, Haramizu teaches treatment of age related motor impairment and weakness (see page 4, paragraphs 1-2, “age related muscle weakness (sarcopenia)”).
Regarding claim 5, Haramizu teaches treatment of age related muscle atrophy and sarcopenia (see page 4, paragraphs 1-2, “age related muscle weakness (sarcopenia)”) and Haramizu in view of Miyoshi and Arimura render obvious treating sarcopenia with Dok-7.
Regarding claim 7, the limitation of “treatment is effective to improve motor function or muscle strength” is a result oriented effect of the method. Haramizu in view of Miyoshi and Arimura render obvious the same method, same agent and same patient population and thus, this result would necessarily be achieved.
Regarding claim 8, the limitation of “wherein the subjects motor function or muscle strength is significantly improved in comparison with a younger subject who is without CMS, MG, MD….” is a result oriented effect of the method. Haramizu in view of Miyoshi and Aurimura render obvious the same method, same agent and same patient population and thus, this result would necessarily be achieved.
Although Haramizu in view of Miyoshi and Arimura does not expressly perform this comparison (with a “younger subject…”), such improvement naturally results of the disclosed method. This comparative relationship therefore exists inherently, and no active measurement is required to practice the claim.
Regarding claim 9, the limitation of “wherein said treatment is effective to reduce age related NMJ denervation ….” is a result oriented effect of the method. Haramizu in view of Miyoshi and Arimura render obvious the same method, same agent and same patient population and thus, this result would necessarily be achieved.
Regarding claim 10, the limitation of “said NMJ denervation is significantly reduced in comparison with a younger ….” is a result oriented effect of the method. Haramizu in view of Miyoshi and Arimura render obvious the same method, same agent and same patient population and thus, this result would necessarily be achieved.
Although Haramizu in view of Miyoshi and Arimura does not expressly perform this comparison (with a “younger subject…”), such improvement naturally results of the disclosed method. This comparative relationship therefore exists inherently, and no active measurement is required to practice the claim.
With respect to the newly added functional limitation requiring “enhancing innervation of neuromuscular junctions”, the limitation does not overcome the rejection. Arimura expressly teaches that administration of AAV DoK7 activates Musk and promotes NMJ formation and enlargement including wild type mice. Thus the prior art teaches the physiological effect underlying the newly recited function. Moreover, to the extent enhancing innervation merely recites the functional result of administering Dok7 according to the otherwise obvious method, such a result would inherently flow from practicing the method where the same Dok7 treatment necessarily produces the disclosed NMJ formation and enlargement. Accordingly merely reciting the resulting function does not patently distinguish the claim method from the combined teachings of the prior art.
Response to Applicant’s Arguments
Applicant argues that neither Haramizu nor Miyoshi teaches or suggests enhancing NMJ innovation in a specifically clean population. Applicant argues that amended claim one is directed to treating age-related motor impairment by enhancing innervation of NMJS in a human subject 60 years age of older without the claimed diseases. Applicant argues that neither Haramizu nor Miyoshi teaches enhancement of NMJ innovation in this patient population.
Applicants arguments have been fully considered but not found persuasive. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Where an applicant’s reply establishes that each of the applied references fails to teach a limitation and addresses the combined teachings and/or suggestions of the applied prior art, the reply as a whole does not attack the references individually as the phrase is used in Keller and reliance on Keller would not be appropriate. This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012) (see MPEP 2145). Haramizu teaches the age-related treatment. Haramizu teaches age-related skeletal muscle atrophy weakness deterioration of NMJ formation and function and age-related muscle weakness or sarcopenia Haramizu further identifies doc seven among the molecules involved in NMJ formation whose age associated decrease is suppressed by its treatment. Haramizu additionally teaches that skeletal muscle decline accelerates after age 60. Thus Haramizu provides the age-related MNJ dysfunction and aged- subject relied upon in the rejection.
Miyoshi teaches the claim type of therapeutic agent mainly administration of an aav vector encoding human Dok7 and demonstrates that increasing Dok7 expression improves NMJ integrity, suppresses motor nerve terminal degeneration at NMJS, suppresses muscle atrophy and improves motor activity.
Arimura teaches that AAV mediated expression of human Dok7 activates Musk and promotes NMJ formation and enlargement. Arimura demonstrates enlargement of NMJs following DOK7 administration and wild type mice thereby demonstrating that the NMJ promoting effect of Dok7 expression is not dependent upon ALS.
The rejection therefore does not require Haramizu alone to disclose Dok7 gene therapy or Miyoshi or Arimura alone to disclose elderly subjects. Rather Haramizu provides the age-related condition and treatment population while Miyoshi and Arimura provide the Dok7 gene therapy teachings and the effects of increasing Dok7 expression on NMJ structure and function.
Applicant argues that Haramizu uses a different class of agent and addresses muscle hypertrophy rather than enhancement of NMJ innervation.
Applicant argues that Haramizu administers a milk fat globule membrane component which is a lipid protein nutritional composition rather than a polynucleotide or gene therapy vector and that Haramizu 's treatment is directed towards increasing muscle mass and suppressing muscle atrophy rather than enhancing NMJ innervation. Applicant's argument has been considered but is not found persuasive. The rejection does not rely upon Haramizu for the teaching of administration of Dok7 polynucleotide. The rejection acknowledges that Haramizu is silent regarding administration of a polynucleotide encoding human Dok7. Miyoshi and Arimura are relied upon to supply that teaching. Haramizu is relevant because it identifies age-related NMJ dysfunction and teaches that molecules involved in NMJ formation expressly including Dok7 undergo an age-associated decrease that is suppressed in treated aging animals. Haramizu therefore provides a relationship between aging and NMJ dysfunction and Dok7 NMJ formation. Miyoshi and Arimura provided the additional teaching that Dok7 expression can be increased directly by administering an aav vector encoding human Dok7 and that doing so promotes or preserves an NMJ structure and function. Arimura is relevant because it teaches that overexpression of Dok7 in skeletal muscle enhances Musk activation and subsequent NMJ formation and that aav Dok7 promotes musk-mediated NMJ formation. Thus, the rejection does not equate MFGM administration with gene therapy. Rather, one reference identifies the age-related NMJ Dok7 problem while the other references teach a known means of increasing Dok7 expression to promote NMJ formation and function.
Applicant argues that a person of ordinary skill would have followed Haramizu's MFGM treatment rather than replacing it with Dok7 gene therapy. Applicant argues that Haramizu already proposes its own solution to the age-related decline in Dok7expression and that a skilled artisan therefore would have continued using MFGM rather than turning to an aav Dok7 gene therapy approach from a different disease.
Applicants arguments have been fully considered but not found persuasive. The fact that Haramizu discloses one treatment for age-related NMJ dysfunction does not establish that a skilled artisan would have lacked reason to consider another known intervention directed to the same NMJ associated pathway Haramizu teaches that aging is associated with NMJ deterioration and an age associated reduction in molecules involved in NMJ formation including Dok7. Miyoshi and Arimura teach that increasing Dok7 expression directly through Dok7 gene delivery produces beneficial effects on NMJ structure.
Arimura provides additional motivation because it characterizes Dok7 mediated NMJ enlargement as a therapeutic approach that may have utility across neuromuscular disorders involving NMJ structural abnormalities. Arimura states that because aav Dok7 enlarges NMJS not only in Dok7 myasthenia mice but also in wild type mice, Dok7 therapy may be applicable to other neuromuscular disorders associated with abnormalities in NMJ structure independent of Dok7 mutations.
Applicant argues that Miyoshi is limited to a pathological ALS model and therefore would not have suggested treatment of otherwise non diseased elderly subject. Applicant argues that Miyoshi employs SOD1 G93A ALS mice and argues that a person of ordinary skill would not have expected results obtained in an ALS model to translate to age-related NMJ impairment in subjects without ALS.
Applicants arguments have been fully considered but not found persuasive. Arimura predates Miyoshi and demonstrates that Dok7 mediated NMJ enlargement is not confined to ALS. Arimura administers aav Dok7 and observes increased NMJ size in wild type mice. Arimura therefore supplies evidence that increased Dok7 expression promotes NMJ enlargement in animals that are not ALS models. Arimura evaluates Dok7 therapy in multiple experimental contexts and concludes that therapies aim to enlarging the NMJ may be useful for a range of neuromuscular disorders. Arimura further states that elevated Dok7 expression that enlarges the NMJ has potential as therapy for a variety of neuromuscular disorders characterized by defects in NMJ structure
Miyoshi is not being relied upon in isolation for a proposition that an ALS specific mechanism necessarily applies to normal aging. Haramizu supplies the aging context while Miyoshi demonstrates beneficial Dok7 effects on NMJ denervation and motor function; and Arimura independently demonstrates that Dok7 mediated NMJ formation enlargement occurs outside the ALS context .
Applicant argues that age-related NMJ dysfunction in ALS NMJ dysfunction are mechanistically different. Applicant relies upon literature discussing differences between age-related denervation reinnervation and associated motor neuron degeneration and argues that the examiner improperly treats aging and ALS as interchangeable.
Applicants arguments have been fully considered but not found persuasive. This argument is not persuasive because the rejection does not require aging and ALS to have identical etiologies or mechanisms. The relevant question is whether the combined teachings would have provided a skilled artisan with reason to employ the known Dok7 intervention in the age associated NMJ dysfunction identified by Haramizu with a reasonable expectation that increased Dok7 expression would beneficially affect NMJ structure or function. Furthermore, Arimura teaches of Dok7 Musk mediated NMJ formation rather than to an ALS specific pathogenic mechanism. Arimura demonstrates that Dok7 expression enhances Musk activation and NMJ formation and the NMJ enlargement occurs even in wild type.
Applicant argues that Miyoshi teaches only suppression or attenuation of ongoing denervation whereas the claimed invention enhances innovation and reinnervation. Applicant argues that Miyoshi would have led a skilled artisan to expect slowing or suppression of continued NMJ denervation at ALS and not affirmative enhancement of NMJ intervention or reinnervation.
Applicants arguments have been fully considered but not found persuasive. Arimura does not describe Dok7 treatment solely in terms of slowing degeneration. Arimura teaches that overexpression of Dok7 enhances activation of Musk and subsequent NMJ formation and reports that aav Dok7 treatment promotes Musk mediated NMJ formation. Arimura further reports clear enlargement of NMJS in wild type mice after treatment. The reference describes stable enlargement of NMJS resulting from Dok7 therapy and discusses an additional possible mechanism involving retrograde signaling from muscle to nerve. Thus, the prior art as a whole taught a structural effect on NMJs from increasing Dok7 expression rather than merely attenuation of ongoing ALS associated degeneration.
Applicant argues that the claimed results were unexpected because age animals exhibited greater innervation than younger untreated animals. Applicant relies upon the reporting finding that AAV Dok7 treated 28 month old mice exhibited less NMJ data version than untreated 24 month old mice and argues that a skilled artisan would have expected at most attenuation of further decline rather than improvement beyond a younger untreated comparison.
Applicants arguments have been fully considered but not found persuasive. The unexpected results must be valued against the scope of the content of the prior as a whole. Arimura already demonstrated before the effect of filing date that increasing Dok7 expression enlarges NMJs including in wild type animals rather than merely preserving diseased NMJs from further deterioration. Arimura further characterizes the resulting NMJ enlargement as stable and identifies elevated Dok7 expression as a potential therapeutic approach for disorders involving NMJ structural defects. The evidence must be weighed against prior teachings that Dok7 expression can promote NMJ formation and enlargement. Applicants comparison to younger untreated animals is evidence relevant to the obviousness determination but it does not establish that enhancement of NMJ structure following Dok7 was contrary to the prior art or unexpected.
Applicant argues that the 132% increase in muscle twitch force above pretreatment baseline was unexpected. Applicant further relies upon an increase in muscle twitch force to 132% of the pretreatment value in aged mice in contrast the result with Miyoshi which applicant inserts did not demonstrate a significant post-treatment improvement in forelimb grip strength.
Applicant’s arguments have been fully considered but not found persuasive. The references provided need not predict the precise numerical magnitude of every physiological result in order to provide a reasonable expectation that the proposed treatment would improve NMJ associated function or motor impairment. Miyoshi teaches improved motor activity following Dok7 therapy while Arimura teaches that Dok7 therapy restores motor activity in Dok7 myasthenia mice and demonstrate stable NMJ enlargement through Musk mediated MNJ formation. Thus, the prior art provided a basis for expecting functional improvement associated with enhanced NMJ structure. Applicants reported magnitude of improvements considered as objective evidence and is weighed with the evidence supporting the prima facie case.
Applicant argues that there was no reasonable expectation of success in treating subjects 60 years or older who do not have the excluded neuromuscular diseases. Applicants arguments have been fully considered but not found persuasive. Haramizu supplies the age-related treatment context and specifically identifies accelerated skeletal muscle decline after age 60. Haramizu further relates aging to deterioration of NMJ function and changes in molecules involved in NMJ formation including Dok7. Miyoshi teaches that increasing Dok7 expression through administration of a Dok7 including aav vector improves NMJ associated outcomes while Arimura demonstrates that Dok7 mediated MNJ formation enlargement is not dependent upon ALS and occurs in wild type animals. Accordingly the references collectively provide a reason to apply the known Dok7 intervention to the age associated NMJ dysfunction identified by Haramizu and provide a reasonable expectation of obtaining an improvement in NMJ structure or function. The rejection does not require reasonable expectation of achieving the precise degree of improvement subsequently reported by applicant rather, the prior art must provide a reasonable expectation (not absolute) of successfully carrying out the proposed combination for its intended purpose (treating age related motor impairment).
Applicant argues that the cited references do not establish the limitations of dependent claims 7-10 inherently. Applicant argues that inherency cannot be established by mere probabilities or possibilities and points to differences between the results obtained in Miyoshi's animals and applicants aged animals.
Applicants arguments have been fully considered but not found persuasive. Miyoshi expressly teaches suppression of NMJ denervation and improvement in motor activity following Dok7 therapy. Arimura especially teaches promotion of Musk mediated NMJ formation and stable enlargement of NMJs following treatment including enlargement in wild type mice. Thus improvement of NMJ structure and associative motor function is supported by express teachings of the cited prior art. The rejection Is based upon the method resulting from the combined teachings, administration of the Dok7 therapeutic taught by Miyoshi (and Arimura) to the age-related patient population and NMJ dysfunction taught by Haramizu. Where the prior art renders obvious the same therapeutic intervention in the same patient population for the same underlying NMJ condition the physiological results that necessarily flow from practicing that method are inherent notwithstanding that the prior art did not expressly measure or characterize those results using the terminology of the claims. Applicants reliance on Miyoshi's animals does not establish otherwise because those animals are not the age-related population to which the proposed combination is directed. Moreover, the other cited art provides evidence supporting the physiological consequence relied upon in the rejection. Arimura demonstrates that aav Dok7 activates Musk and promotes NMJ formation enlargement even in wild type mice thereby showing that the NMJ promoting activity of Dok7 is not confined to the ALS disease state. Accordingly the inherency determination is not based upon mere possibility or probability. Haramizu supplies the age-related NMJ context, Miyoshi supplies the administration of Dok7 as a therapeutic and its beneficial effects on NMJ integrity and motor function and Arimura independently evidences that Dok7 itself promotes Musk mediated NMJ formation and enlargement outside the ALS. When the Dok7 therapeutic is administered to the age-related population in accordance with the method rendered obvious by the combined teachings, the resulting improvement in NMJ structure/function is a natural consequence of that method.
Applicant argues that the dependent claims remain non obvious because Miyoshi's results differ from the aged mouse results. Applicant argues that because Miyoshi produced only partial rescue in an ALS model and did not produce the same strength or comparative innervation results observed in the aged mice the dependent claims are not rendered obvious. Applicants arguments are fully considered but not found persuasive. In particular this argument is not persuasive with respect to the limitations directed generally to improving better function muscle strength and NMJ structure, or reducing degeneration because these effects are taught or reasonably suggested by the combined references. Miyoshi demonstrates beneficial effects on NMJ integrity muscle atrophy and motor function. Arimura additionally demonstrates Musk mediated NMJ formation enlargement and shows that the structural NMJ effect occurs outside the ALS context.
Applicant relies on later published Moss et al. Applicant acknowledges that Moss was published after June 4th 2020 effective filing date and states that moss is not being used as prior but is a later scientific summary of pre priority literature,
The later published Moss reference has been considered to the extent appropriate for applicants argument concerning the state of scientific knowledge. However, the obviousness determination is based upon what the prior would have taught or suggested to a person of ordinary skill in the art before the effective filing date. Arimura itself directly teaches that Dok7 mediated NMJ enlargement is not confined to ALS. Arimura demonstrates enlargement in wild type mice and expressly proposes broader application of Dok7 mediated NMJ enlargement to neuromuscular disorders involving NMJ abnormalities. Arimura provides prior evidence relevant to whether a skilled artisan would have regarded the effects of Dok7 expression as limited to an ALS environment. For all the reasons stated above, the rejection is maintained.
Conclusion
No claims are allowed.
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/ERINNE R DABKOWSKI/ Primary Examiner, Art Unit 1654
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