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 .
Status of Claims
The amendment filed on 04/27/2026 amended claim 18, cancelled claims 1-17, and added new claims 19-25. Claims 18-25 are pending. Claims 18-25 will be examined on the merits.
Election/Restrictions
Applicant’s election without traverse of Group I, claim 18, in the reply filed on 04/27/2026 is acknowledged. As all Group I claims were cancelled, no claims are withdrawn.
Information Disclosure Statement
The Information Disclosure Statements filed on 11/27/2023, 9/05/2024, and 4/27/2026 have been considered. Signed copies are enclosed.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 19, 20, and 24 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.
Claim 19 recites the antibody defined by the CDRs of claim 18 “binds to at least one epitope selected from the group consisting of a fragment of amino acids at positions 53 to 72, a fragment of amino acids 101 to 123, a fragment of amino acids 135 to 159, a fragment of amino acids 135 to 155, a fragment of amino acids 218 to 228, and a fragment of amino acids 259 to 269 from the N-terminus of the ASM protein.” This recitation is indefinite, as there is no sequence provided for the recited ASM protein, and one would not reasonably be able to determine the metes and bounds of the claim when the claim references positions in an undisclosed sequence. Examiner notes that the SEQ ID NOs provided in claim 22 further limit the sequence of the ASM protein, but claim 19 does not depend from claim 22, and therefore no ASM sequence is present in the recitation of claim 19. Therefore, claim 19 is indefinite.
Claim 19 recites that the antibody defined by the CDRs of claim 18 “binds to at least one epitope selected from the group…”, and claim 20 also recites the antibody “binds to at least one epitope selected from the group…” while providing an alternate group of epitopes. However, antibodies defined by CDRs are generally accepted in the art to only recognize one epitope (see Janeway, Immunobiology, Chapter 3.6-9, Written description below). Therefore, the antibody recited in claim 18 cannot bind to more than one epitope recited in the claim. The phrasing of “binds to at least one” implies the antibody may bind to more than one of these epitopes, which leads to the claim being indefinite, as one of reasonable skill in the art would know that the antibody of claim 18 cannot bind to more than one of these epitopes, and therefore cannot determine the appropriate scope of the claims.
Claim 24 recites “wherein in the degenerative brain disease, the expression or aggregation level of amyloid-3 is higher or at risk of being higher than normal”. The term “higher than normal” in claim 24 is a relative term which renders the claim indefinite. The term “normal” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As neither the instant claim nor the specification provide a definition for 'normal' levels of amyloid-B, one would not reasonably be able to determine when a patient has higher expression or aggregation levels of amyloid-B than 'normal'. Moreover, neither the specification nor the instant claims provide a definition or any limitation for determining if a degenerative brain disease for "at risk of being higher than normal". There is no way for a person skilled in the art to know if a subject would be included in the scope of claim 24. Therefore, claim 24 is indefinite.
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 18-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 18-25 are drawn to a method for preventing, alleviating, or treating a brain disease, comprising administering to a subject an antibody that specifically binds to acid sphingomyelinase (ASM) protein. The anti-ASM antibody of claim 18 has a recited set of CDRs. Claims 19 and 20 are drawn to the epitope targeted by the antibody. Claims 21 and 22 further define the ASM protein. Claims 23-25 further define the brain disease as a degenerative brain disease, with high levels of amyloid-B expression or aggregation, or as one of the degenerative brain diseases provided in a list.
The specification teaches the antibody of claim 18, with an HCR1 of SEQ ID NO: 31, HCR2 of SEQ ID NO: 32, HCR3 of SEQ ID NO:33, and an LCR1 of Seq ID NO: 49, LCDR2 of SEQ ID NO: 50, and LCDR3 of SEQ ID NO: 51. The specification refers to this particular antibody as #9104 on page 37, in Table 3. The specification identifies that this #9104 antibody binds to the epitopes of SEQ ID NO: 68 and 70 on page 43, Table 8, and Figure 3. The specification provides the following definition for ‘epitope’ on page 13: “As used herein, the term "epitope" refers to a specific site of an antigen that can be recognized by an antibody, and means an antigenic determinant to which an antibody can specifically bind. The epitope is commonly used as the same meaning as a determinant or an antigenic determinant.” The specification also teaches the use of the #9104 antibody in treating/alleviating Alzheimer’s disease, inhibiting ASM protein activity in primary human cells and demonstrating a reduction of symptoms in a mouse model of Alzheimer’s disease (Examples 4 and 6+).
Based on the evidence presented in the specification, Applicant has sufficient written description to support a claimed method for treating or alleviating Alzheimer’s disease comprising administering the recited antibody. Additionally, the recited antibody meets the written description provision of 35 U.S.C. 112(a). However, the claims encompass far more than a method for treating or alleviating Alzheimer’s disease, and Applicant does not have sufficient written description to support a method of preventing, alleviating, or treating any brain disease. Additionally, there is not sufficient support provided in the specification for all the epitopes recited in claims 19 and 20.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The state of the art regarding degenerative brain diseases is discussed by Lamptey et al (Int. J. Mol. Sci. 2022, 23, 1851). Lamptey et al. outline the complex nature of neurodegenerative disorders, with few successes with long-term benefits (see abstract). Lamptey emphasizes the diversity in pathogenesis between these diseases, and states there is no single treatment for all neurodegenerative diseases. As there is no existing body of art outlining treatment for all neurodegenerative diseases, and therefore no existing body of art outlining treatment for all brain diseases, there is no precedent that the claimed invention can build on. Therefore, the invention would need to be demonstrated to treat more diseases than just Alzheimer’s disease in order to provide written description support for a method of treating any brain disease, or any neurodegenerative disease (see enablement rejection below for more regarding the state of the art). Therefore, Applicant does not have sufficient written description to support the broad claim of any brain disease, as recited in claim 18.
Additionally, the state of the art regarding antibodies generally accepts that CDRs determine specificity for a single epitope (Janeway, Immunobiology, Chapter 3.6-9). Claim 19 recites six possible epitopes for the antibody with specific CDRs recited in claim 18, and recites the antibody binds to “at least one of” these epitopes. This language implies that the CDR may bind to more than one of these epitopes. This is inconsistent with the state of the art, and the specification does not provide sufficient support that the antibody of claim 18 can bind to any of these six epitopes. Similarly, claim 20 recites six epitopes the antibody with specific CDRs recited in claim 18 may bind to. This claim has the same issue, in that there is not sufficient support that the antibody of claim 18 can bind to any of these six epitopes. Therefore, claims 19 and 20 do not have written description support as currently written.
Applicant is reminded that Vas- Cath makes clear that the written description provision of 5 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is severable from its enablement provision. (See page 1115).
Claims 18-25 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 of treating Alzheimer's disease, does not reasonably provide enablement for a method for preventing, alleviating, or treating any brain disease. 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.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized in In re Wands (858 Fed 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, limited working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to make and use the claimed invention.
Claims 18-25 are broadly drawn to a method for preventing, alleviating, or treating a brain disease. “A brain disease” is defined in the specification, on page 25, to be all types of brain diseases known in the art. This method comprises administering to a subject an antibody that specifically binds to acid sphingomyelinase (ASM) protein. The antibody of claim 18, with an HCR1 of SEQ ID NO: 31, HCR2 of SEQ ID NO: 32, HCR3 of SEQ ID NO:33, and an LCR1 of Seq ID NO: 49, LCDR2 of SEQ ID NO: 50, and LCDR3 of SEQ ID NO: 51, is referred to in the specification as #9104, and examples 4 and 6 demonstrate that the antibody inhibits ASM activity. Treatment with an antagonistic antibody will only work on diseases that are cause, in full or in part, by overactivity of the target protein (in this case, acid sphingomyelinase, or ASM).
The art regarding the causes of neurodegenerative diseases is still developing; additionally the role of ASM in many of these diseases is still being elucidated (see Alessenko and Albi, 2020, Front. Neurol. 11:437). ASM is known to play a role in the pathogenesis of Alzheimer’s disease, as recited in the instant specification (pages 2-3) and in Alessenko and Albi (pages 3-6). In this case, the claimed invention is enabled by the specification in examples 4-10. However, neither the specification nor the art support that the invention is enabled for all brain diseases. The specification provides no working examples beyond Alzheimer’s disease. Treatment of neurogenerative diseases by antibodies is limited, as antibodies have difficulties crossing the blood-brain barrier (Neves et al., 2016, Trends in Biotechnology 34.1: 36-48). As the art does not support all degenerative brain diseases being treated with antibodies, or the role of ASM in all degenerative brain diseases, the art does not enable the current invention beyond the working examples.
Regarding the list of diseases provided in claim 25, ASM is not known to play a role in all the named diseases (see Alessenko and Albi, whole document). Moreover, some of the named diseases would not be treatable using an antagonistic anti-ASM antibody. For example, Niemann-Pick disease is hallmarked by deficiency in ASM (McGovern et al., Orphanet journal of rare diseases 12,1 41). An antibody that inhibits the function of ASM would not work to treat a disease like Niemann-Pick, as there is no ASM present in the subject for the antibody to inhibit. Similarly, Lewy body dementia and frontotemporal dementia, both neurodegenerative diseases listed in claim 25, are hallmarked by impaired ASM activity already (Usenko et al., Mol Neurobiol 59, 2277–2287 (2022) and Boyle et al., Neurobiology of disease 213 (2025): 107024). As these diseases stem from impaired ASM function, it does not follow that treating with an ASM inhibitory antibody would treat the disease. Huntington’s disease, also named in claim 25, is associated with altered sphingolipid metabolism, but typically caused by a different metabolic pathway, as outlined in Pepe et al. (Molecular Therapy 31.1 (2023): 282-299.). Therefore, there is no reason to believe that treatment with an anti-ASM antibody would treat a subject with Huntington’s disease. Finally, even when ASM is possibly implicated in a disease, such as Parkinson’s disease, as recited in Alessandro and Albi, there are often conflicting reports on how much of a rule ASM plays (see Signorelli et al., Biomolecules 11.9 (2021): 1311). For example, some studies have shown that loss-of-function mutations in the SMPD1 gene, which encodes ASM, leads to worsening Parkinson’s disease (Alcalay et al., Movement Disorders 34.4 (2019): 526-535.). Therefore, there is no guarantee that targeting ASM activity with an anti-ASM antibody would treat Parkinson’s disease.
Taken together, the art is not enabling for the full breadth of claim 18, nor the limitation of degenerative brain diseases as recited in claim 23, or the list of diseases in claim 25.
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.
Claims 18-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/564510 in view of US-2016/0101070-A1.
Claims 18-25 are drawn to a method for preventing, alleviating, or treating a brain disease comprising administering the recited antibody. ‘510 recites the same antibody the instant claims (see claims 1-11). ‘070 discloses the use of an ASM activity inhibitor for preventing or treating neurological diseases. It would be obvious for one of ordinary skill in the art to administer the antibody of ‘510 in order to treat a brain disease, as in ‘070. Therefore, ‘510 in view of ‘070 renders the claimed invention obvious.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/AMELIA STEPHENS/Examiner, Art Unit 1645
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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