CTNF 17/929,609 CTNF 89441 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. 07-06 AIA 15-10-15 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. Election/Restrictions 08-25-01 AIA Applicant’s election without traverse of Group I (claims 1, 4, 6, 8-11, 13-14, 20, 22, 36-41, 48, 50-52, 57, 59, 61, and 63-65) , in the reply filed on 12 September 2025 , is acknowledged. Applicants’ compliant species election: “Aralast NP™” (an “A1AT agent” per claim 1) retrieved no applicable prior art reference. See “SEARCH 6” in enclosed search notes. The Examiner extended the Markush search to: “mRNA molecule” as an “A1AT agent” per claim 1), which search did retrieve prior art. See “SEARCH 7” in enclosed search notes. Therefore, the Markush search will not be extended unnecessarily to other “agents” in this Office Action per Markush search practice. Claims 1, 9-11, 13, 48, 50-51, and 59 read on the extended Markush search. 08-06 AIA Claim s 4, 6, 8, 14, 20, 22, 36-41, 52, 57, 61, and 63-65 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species of “agent” , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12 September 2025 . 08-06 AIA Claim s 2-3 and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention of Group II , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12 September 2025 . Please cancel these non-elected Group II claims to expedite allowance since a non-elected composition Group II cannot be rejoined under rejoinder practice. Note that had Applicants elected the composition Group II, then the method of use Group I could be rejoined . 08-06 AIA Claim s 45 and 47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention of Group III , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12 September 2025 . 08-06 AIA Claim 46 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention of Group IV , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12 September 2025 . Please cancel non-elected Groups III-IV to expedite allowance as these groups cannot be rejoined since they do not contain all of the limitations of elected Group I per rejoinder practice . 08-23-02 AIA Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i). Current Status of 17/929,609 This Office Action is responsive to the amended claims of 12 September 2025. Claims 1, 9-11, 13, 48, 50-51, and 59 have been examined on the merits. Claims 1, 11, and 51 are original. Claims 9-10, 13, 48, 50, and 59 are previously presented. Priority The effective filing date is 2 March 2020. Information Disclosure Statement (IDS) As of December 9, 2025, there is no IDS on file for the Examiner to consider. Claim Rejections - 35 USC § 102 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-15 AIA Claims 1, 9-11, 13, and 59 are r ejected under 35 U.S.C. 102(a )(1) as being a nticipated b y: F ACTOR (U.S. 2019/0307897 A1). This prior art rejection is inspired by the Written Opinion for PCT/US2021/020537. The prior art reference FACTOR teaches a method of treating amyotrophic lateral sclerosis (ALS) in a human subject (para [0182]: the subject is a human) in need thereof comprising administering to the subject an agent in an amount effective to: 1) increase an alpha-1 anti-trypsin (A1AT) activity in a target cell, tissue, or organ of the subject (para [0063]: FACTOR teaches a method for treating A1AT deficiency; FACTOR para [0212] provides methods for treating ALS by administering therapeutics comprising nucleic acids and/or cells; para [0063]; para [0070]: this method provides for reversing alpha-1 antitrypsin (A1AT) deficiency in a cell—wherein the subject has hypofunctional A1AT activity), wherein the subject is characterized as having insufficient alpha-1-anti-trypsin activity in the target cell, tissue, or organ (para [0070]). This anticipates instant claims 1 and 59 . Furthermore, said treatment involves treating the liver (hepatocyte cells) (see reference claims 41-45) thereby anticipating instant claims 9-11 . Said treatment involves using mRNA formulated into lipid nanoparticles (see para [0298] and Table 1) as the A1AT agent (scope of Markush search extension), thereby anticipating instant claim 13 . Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim (s) 1, 9-11, 13, 48, 50-51, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over : FACTOR (U.S. 2019/0307897 A1), in view of: YEDA (U.S. 2015/0164891 A1), in further view of: ERIKSSON (U.S. 2008/0171394 A1), and in further view of: LU (Lu, et al. “Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis.” Neurology , (1 May 2015)), Vol. 84, No. 22, pp. 2247-2257). This prior art rejection is inspired by the Written Opinion for PCT/US2021/020537. The instant claims 1, 48, and 50-51 are drawn to a method of treating ALS by administering an agent that increases an A1AT activity (claim 1) AND a method of measuring and comparing a first concentration of alpha-1 anti-trypsin and comparing that to a second concentration of neurofilament by the method of claims 48 and 50-51 to select the patient for A1AT treatment of ALS. Determining the scope and contents of the prior art : The prior art reference FACTOR teaches instant claims 1, 9-11, 13, and 59 , see, above. Recall, too, that FACTOR teaches treating the liver (hepatocyte cells) (see reference claims 41-45) thereby teaching instant claims 9-11 . By deductive reasoning, treating the liver is only required when the liver has an impaired activity or function, thereby teaching instant claim 50 . The prior art reference YEDA teaches a method for identifying a subject suitable for treatment of ALS (YEDA teaches a method for diagnosing a motor neuron disease (MND), the method comprising analyzing in a sample of a subject in need thereof-para [0049]; the motor neuron disease comprises ALS-para [0057]), wherein the value above a threshold value selects the subject for treatment (wherein a down-regulation in said (i) or (i)/(ii) beyond a predetermined threshold is indicative of the MND-para [0379]; the motor neuron disease comprises ALS-para [0057]). The prior art reference ERIKSSON teaches biological markers for monitoring disease progression (para [0001]) and teaches measuring a first concentration of an alpha-1 anti-trypsin in a biological sample from the subject (the method comprises measuring the level of phosphorylation of a marker in a biological sample from the subject in a first sample, wherein the marker is selected from the group consisting of a A1AT, para [0080]); b. measuring a second concentration in the sample; and c. determining a value comprising the ratio of the first concentration to the second concentration (measuring the level of phosphorylation of the marker in a biological sample from a second sample; and comparing the phosphorylation level of the marker measured in the first sample with the phosphorylation level of the marker measured in the second sample-para [0080]). The prior art reference LU teaches cerebrospinal fluid (CSF) neurofilament light chain (NfL) levels in relation to disease progression and survival in ALS (Abstract). Furthermore, LU teaches a concentration of a neurofilament in a sample (CSF NfL levels were higher in ALS-fast than in ALS slow-pg. 2252, left-hand column, first paragraph). Thus, LU teaches that neurofilaments are a prognostic/diagnostic biomarker for ALS (Abstract). Ascertaining the differences between the prior art and the claims at issue : FACTOR fails to explicitly teach the method of instant claim 48. YEDA fails to explicitly teach a method comprising: a. measuring a first concentration of an alpha-1 anti-trypsin in a biological sample from the subject; and b. measuring a second concentration of a neurofilament in the sample; and c. determining a value comprising the ratio of the first concentration to the second concentration. Furthermore, YEDA and ERIKSSON fail to explicitly disclose concentrations of a neurofilament in the sample. ERIKSSON fails to explicitly teach every step of instant claims 1 and 48. Furthermore, YEDA and ERIKSSON fail to explicitly disclose concentrations of a neurofilament in the sample. LU fails to explicitly teach instant claim 1 and all the steps of instant claim 48. Resolving the level of ordinary skill in the pertinent art : The artisan is a medicinal scientist or clinician with knowledge in how to diagnose ALS, prescribe treatment/therapy for ALS, and monitor the prognostic value of the therapy in an ALS patient. The artisan is also knowledgeable in how to monitor ALS disease progression. Considering objective evidence present in the application indicating obviousness or nonobviousness : The instant claims 1, 48, and 50-51 are prima facie obvious in light of the combination of references FACTOR, YEDA, ERIKSSON, and LU. The artisan would be motivated to modify the teachings of YEDA with the teaching of ERIKSSON for the purpose of diagnosing a disease, monitoring its progression, and assessing response to therapy (ERIKSSON para [0014]) since the artisan needs to know if the patient has a disease and its progression and determine how the prescribed therapy is improving patient prognosis. The artisan would be expected to use the teachings of YEDA and ERIKSSON to diagnose disease, monitor disease progression, and assess patient response to therapy during the normal course of disease management since these references already layout what is known in the art regarding disease diagnosis and monitoring. Thus, from the combination of YEDA and ERIKSSON, the artisan would arrive at much of the procedure disclosed in instant claim 48, namely: measuring a first concentration of an alpha-1 anti-trypsin in a biological sample from the subject (ERIKSSON para [0080]); b. measuring a second concentration in the sample; and c. determining a value comprising the ratio of the first concentration to the second concentration (ERIKSSON para [0080]). Furthermore, the artisan would be motivated to modify the teachings of YEDA (now combined with ERIKSSON, above) with the teaching of LU for the purpose of using blood-derived neurofilament light chain (interpreted as equivalent to “neurofilament” under the broadest reasonable interpretation) level as an easily accessible and art-recognized biomarker with the prognostic value in ALS (LU, Abstract). The artisan would be expected to use blood-derived neurofilament levels as an easily accessible and art-recognized biomarker with prognostic value for ALS (per LU, Abstract) in the normal course of diagnosing disease, monitoring its progression, and assessing patient response to therapy per the teachings of LU (see, above). Thus, the artisan is using the neurofilament as a biomarker for ALS. As such, the combination of YEDA, combined with ERIKSSON, and LU would inevitably lead the artisan to measure a first concentration of biomarker in a biological sample, and a second concentration (the neurofilament – which is prognostic for ALS) of a biomarker in the sample, and comparing the first with the second concentration will lead to a value, above which selects the subject for treatment. This teaches instant claim 48 . Recall, too, that the prior art reference FACTOR teaches treating the liver (hepatocyte cells) (see reference claims 41-45) thereby teaching instant claims 9-11 . By deductive reasoning, treating the liver is only required when the liver has an impaired activity or function, thereby teaching instant claim 50 . Moreover, the artisan would be motivated to and expected to diagnose liver impairment by measuring compounds secreted by the liver, such as steroid hormone levels, bile acid production, or production of: cholesterol, lipid, HDL, LDL, triglycerides, or cytokines (per Applicant claim construction showing instant claim 51 depending from instant claim 50). This deductive reasoning permits rejecting instant claims 50-51 because instant claim 48 is rejected, above. Conclusion No claims are presently allowable as written. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN S KENYON whose telephone number is (571)270-1567. The examiner can normally be reached Monday-Friday 10a-6p. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /JOHN S KENYON/Primary Patent Examiner, Art Unit 1625 Application/Control Number: 17/929,609 Page 2 Art Unit: 1625 Application/Control Number: 17/929,609 Page 3 Art Unit: 1625 Application/Control Number: 17/929,609 Page 4 Art Unit: 1625 Application/Control Number: 17/929,609 Page 6 Art Unit: 1625 Application/Control Number: 17/929,609 Page 7 Art Unit: 1625 Application/Control Number: 17/929,609 Page 8 Art Unit: 1625 Application/Control Number: 17/929,609 Page 9 Art Unit: 1625 Application/Control Number: 17/929,609 Page 10 Art Unit: 1625 Application/Control Number: 17/929,609 Page 11 Art Unit: 1625