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 .
Application Status
The amended claims filed with the Response to the non-final Office Action on April 3, 2026 are acknowledged. Claims 1, 3-4, and 9-21 are pending. Claims 5-8 are canceled. Claims 1, 4, and 14 are amended. Claims 19-21 are newly added. Claims 9-18 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1, 3-4, and 19-21 are under examination herein.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). With the amendment to the specification filed April 3, 2026, page 7 recites a first protein linker sequence of “GGGGS” without a corresponding sequence identifier (SEQ ID NO:) (in the third-to-last paragraph) and a second protein linker sequence of “GGGGS” attributed to SEQ ID NO: 20 (in the second-to-last paragraph). The CRF Sequence Listing and Table 1 of the specification (at page 21) recite that the sequence corresponding to SEQ ID NO: 20 is the amino terminal domain of GluN2B, not a protein linker comprising the amino acid sequence of “GGGGS”.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
WITHDRAWN OBJECTIONS AND REJECTIONS
The prior grounds of objection over the specification are withdrawn in view of Applicant's amendments to pages 110 and 111.
All prior rejections of claims 5-8 are rendered moot by the cancelation of the claims.
The rejection of claim 4 under 35 U.S.C. § 112(b) is withdrawn in view of Applicant's claim amendments thereto.
The rejection of claims 1 and 3-4 under 35 U.S.C. § 112(a) as failing to comply with the written description requirement is withdrawn in view of Applicant's amendments to claim 1.
MAINTAINED CLAIM REJECTIONS
Claim Rejections - 35 USC § 103
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.
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.
(1)
Claims 1, 3, and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Sharma (BMC Biotechnology (2018) 18:41; cited in PTO-892 mailed December 2025) in view of Sansing (Nat Clin Prac Neurol (2007) 3(5): 291-296; cited in PTO-982 mailed December 2025) and Vincent (US 2017/0153234 A1; cited in PTO-892 mailed December 2025). This is a maintained rejection that has been updated to reflect Applicant's amendments to the claims.
Sharma teaches that detection of anti-NMDA receptor encephalitis (ANRE) autoantibodies in CSF is essential for diagnosis of ANRE, and that full recovery is possible if therapy is initiated early in the disease course (Abstract). Sharma further teaches that a cell line that stably expresses pathogenic NMDAR epitopes could improve standardization of assays for detecting anti-NMDAR encephalitis. To this end, Sharma generated a cell line expressing an amino terminal domain (ATD) fusion protein comprising the amino terminal domain of GluN1 NMDAR subunit (NR1), a Myc epitope tag (EIDSEEKL), a 6xHIS tag, and a Tobacco Etch Virus (TEV) protease cleavage site (ENLYFQFF), fused to the platelet derived growth factor receptor (PDGFR) receptor transmembrane domain (e.g., Abstract; Results, page 2; Figure 1). (As recited on page 14 of Applicant’s disclosure, a Myc-tag or a HIS-tag can be used as a capture domain.) Sharma states that the Myc tag and 6xHIS tag provide functionality for immunoassays and antigen purification (e.g., Abstract). Sharma illustrates that the ATD fusion protein was bound by ANRE patient monoclonal antibodies (e.g., Results, pages 2-3; Table 1) and maintained reactivity with ANRE patient autoantibodies using immunofluorescence and ELISA assays (e.g., Results, pages 3-5).
However, Sharma does not teach an ATD fusion protein that further comprises an ECD fragment of at least one of the NMDAR subunits GluN2A, GluN2B, GluN2C, or GluN2D, comprising at least an ATD.
Sansing describes a case study of a patient diagnosed with encephalitis associated with NMDAR antibodies. Sansing discloses, “NMDAR antibodies are present in serum and CSF, usually with intrathecal synthesis, and are sometimes only detected in the CSF. The main target epitopes are in the NR1/NR2 heteromers of the NMDAR. The major antigen is NR1/NR2B, which is predominantly expressed in the hippocampus and forebrain, but reactivity with other NR1/NR2 heteromers is frequently observed. In the present case, the patient had serum and CSF antibodies that reacted with all NR1/NR2 heteromers (NR2A–NR2D)” (“Discussion of Diagnosis”). Sansing further sets forth, “Antibodies to NR2 subunits of the NMDAR have been reported in several other disorders. These antibodies (IgG or IgM) target linear epitopes (detectable by immunoblot), often in the intracellular domain. By contrast, the IgG antibodies of patients with paraneoplastic anti-NMDAR encephalitis target conformal extracellular epitopes of NR1/NR2 heteromers (not detectable by immunoblot), and are likely to be pathogenic” (“Differential Diagnosis”).
Vincent discloses methods of determining whether an individual has or is likely to develop a neurological disease (e.g., Abstract). Said method comprises detecting the presence or absence of one or more autoantibodies against the γ subunit of the GABA receptor in the individual, where the presence or one or more autoantibodies indicates that the individual has or is more likely to develop the disease, e.g., autoimmune encephalitis (e.g., ¶ 0004-0005; claims 1-2 and 7-8). The methods of detecting autoantibodies from a sample derived from the individual include ELISA, fluorescence microscopy, and fluorescence-activated cell sorting (FACS) (e.g., ¶ 0027-0052; claims 11-12). In certain embodiments, Vincent teaches that the invention is drawn to multiplex detection of two or more autoantibodies, each of which is directed against a different antigen, wherein the preparation comprises the γ2 subunit of the GABAA receptor together with additional antigens relevant to the diagnosis of neurological disease selected from, e.g., NR1, NR2A, and NR2B (e.g., ¶ 0058-0060).
In view of the above, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to generate a NMDAR protein construct comprising one or more autoantibody epitopes, wherein said construct comprises a GluN1 (NR1) ATD, at least an NR2B, or NR2B and NR2A, or NR2B, NR2A, and NR2C ATD, and a capture domain, which could be useful for detecting anti-NMDAR encephalitis. The skilled artisan would have been motivated to do so because Sharma teaches that early detection of autoantibodies in anti-NMDAR encephalitis is critical for diagnosis and beginning treatment early enough to ensure full recovery for the patient. Further, Sansing sets forth that antibodies to NR1 and all of the NR2 subunits are detectable in at least some patients with anti-NMDAR encephalitis. There would have been a reasonable expectation of success because, as set forth by Vincent, methods of detecting the presence or absence of one or more autoantibodies (including NR1 and NR2A and/or NR2B and/or NR2C) have been described in the art for the purpose of determining whether an individual has or is likely to develop a neurological disease such as an autoimmune encephalitis.
Response to Arguments
Applicant's arguments filed April 3, 2026 have been fully considered but they are not persuasive.
Applicant submits that in view of the amendments to claim 1, the combination of cited references of Sharma, Sansing, and Vincent would not have led to the instantly claimed protein construct. With respect to Sharma, Applicant states that Sharma does not disclose an NMDAR protein construct comprising at least a GluN1 ATD in combination with a GluN2 ECD fragment. Applicant states that Sansing does disclose an NR1-NR2A/B/C/D heterodimer construct, but that the construct comprises “the entire ECD and not fragment comprising the specific ATDs of the GluN1 and GluN2 submits as claimed”, and that no data are provided for the function of such constructs. Applicant further submits that Vincent discloses a test for autoimmune encephalitis based on multiplex detection of two or more autoantibodies, and that “no NR1-NR2 construct is described”. Applicant concludes that none of the cited references describe “the combination of ATD-NR1 with ATD-NR2 in a fusion protein construct” and that Sansing and Vincent do not address the ATD, as the entire ECD is used. Remarks at pages 8-9.
Applicant further submits that the instantly claimed NMDAR protein construct demonstrated unexpected experimental results, with “NR1-ATD-N2B-ATD-Fc displaying the highest sensitivity, detecting 5 out of 6 autoantibody types, thus providing an unexpected improvement in detection capability, also when compared to other constructs”. Applicant points at least to Figures 8-10 for support. Remarks at pages 10-11.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It is held that, using Sharma as a starting point, one of ordinary skill in the art could have arrived at a fusion protein comprising an NR1 ATD and a capture domain, which further comprises autoantibody epitopes for additional NMDAR subunits (i.e., one or more of NR2A, NR2B, NR2C, and NR2D) based on the further teachings of Sansing and Vincent. There would have been a motivation to do so since Sansing provides that antibodies to NR2 subunits are reported in several disorders, making a construct against multiple autoantibodies useful. Vincent provides a proof-of-concept that a preparation comprising two or more autoantibody epitopes is achievable. Furthermore, it is noted that even if Sansing or Vincent do not expressly teach a fragment comprising just the ATD, it is understood by those of ordinary skill in the art that the NR1 and NR2 ECDs comprise a fragment thereof that corresponds to the ATD, which falls within the scope of the present claims.
With respect to Applicant's assertion of unexpected results, these arguments are not found to be persuasive because the instantly claimed fusion protein (N1-ATD-N2B-ATD-Fc) shows variable performance compared to the combination of the two monospecific constructs N1-ATD-Fc + N2B-ATD-Fc (e.g., Figures 4, 8, 10), and/or to a construct comprising N1ecd-N2Becd-Fc (e.g., Figure 3 of Drawings), performing about the same, better, or worse. The Drawings do not provide any statistical information to contextualize the significance of any apparent effect.
For these reasons, the rejection is maintained.
(2)
Claims 1 and 3-4 are rejected under 35 U.S.C. 103 as being obvious over Sharma (BMC Biotechnology (2018) 18:41; supra) in view of Sansing (Nat Clin Prac Neurol (2007) 3(5): 291-296; supra) and Vincent (US 2017/0153234 A1; supra) as applied to claims 1, 3, and 19-21 above, further in view of Egland (US 2015/0268241 A1; cited in PTO-892 mailed December 2025). This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
The teachings of Sharma are recited in the 35 U.S.C. § 103 rejection above.
However, Sharma does not teach an ATD fusion protein comprising an antibody Fc fragment as the dimerization domain/capture domain.
The teachings of Sansing and Vincent are set forth in the 35 U.S.C. § 103 rejection above.
Egland provides compositions including reagents for detecting human autoantibodies against at least two different proteins for use in detecting breast cancer (e.g., Abstract). The disclosed antibody detection markers can be in the form of an Fc fusion protein designed to have native conformations and can have between 2 and 20, 4 and 10, and 5-10 antibody detection markers (e.g., ¶ 0003, 0023, 0047-0058). In an exemplary embodiment, the Fc fusion protein comprises a HER2 ECD and Fc (e.g., 0013; 0055-0058; Figure 1).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to generate a protein construct, which comprises an immunoglobulin Fc domain as the capture domain, for the purpose of detecting anti-NMDAR autoantibodies, wherein one monomer is formed from the ECD of GluN1 (or a fragment thereof) and another is formed from the ECD of a GluN2 subunit because the Fc heterodimer would create non-covalent conformational extracellular epitopes of NR1/NR2 heteromers for detecting anti-NMDAR autoantibodies. These conformational extracellular epitopes of NR1/NR2 heteromers are not detectable by immunoblot and are likely to be pathogenic. The skilled artisan would have been motivated to do so because antibodies to multiple NMDARs and their heterodimer conformational epitopes are observed in anti-NMDAR encephalitis patients (as demonstrated, e.g., by Sansing) and early detection ensures that patients can begin treatment earlier. Furthermore, it is routine in many contexts to detect more than one autoantibody simultaneously to characterize the disease. There would have been a reasonable expectation of success because Egland describes exemplary autoantibody detection reagents which are Fc fusion protein constructs, and while the invention of Egland is drawn to detecting breast cancer, known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on market forces if the variations are predictable to one of ordinary skill in the art.
Response to Arguments
Applicant's arguments filed April 3, 2026 have been fully considered but they are not persuasive.
With respect to the further teachings of Egland, Applicant submits that the autoantibody-Fc constructs taught by Egland do not comprise any ATD for NR1 or NR2, and that while Egland teaches an ECD of a breast cancer marker protein, “it does not suggest the combination of a Fc-domain with an anti-NMDAR- heterodimer-construct comprising an ATD-NR1 and an ARD-NR2 subunit”. Remarks at pages 10-11.
In response, it is held that while the teachings of Egland are not drawn specifically to NMDAR-containing Fc constructs, Egland would be considered analogous art due to its relevance to the field of human autoantibody detection. Egland provides a further proof-of-concept of autoantibody-Fc fusion constructs having two or more detection markers, and furthermore, one of ordinary skill in the art applying the teachings of Egland would recognize that the Fc domain offers an alternative suitable option as the dimerization/capture domain.
For these reasons, the rejection is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703)756-1420. The examiner can normally be reached Monday to Friday, 9:30am - 6:00pm EST.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
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