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 Response to the Restriction Requirement filed on October 8, 2025 has been entered. Applicant's election without traverse of the invention of Group I (claims 1 and 3-8) is acknowledged.
Claims 1 and 3-18 are pending. Claims 9-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1 and 3-8 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). Specifically, protein linker sequences of “GGGGS” appear on page 7 without a corresponding sequence identifier (SEQ ID NO).
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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See page 111. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term “TWEEN®”, which is a trade name or a mark used in commerce, has been noted in this application. See page 110. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
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 4, 6, and 8 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.
Regarding claims 4 and 6, the phrase "preferably" renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Examples and preferences in a claim may lead to confusion over the intended scope of the claim. The description of examples or preferences is properly set forth in the specification rather than the claims.
It is noted for Applicant that preferred limitations will not be treated as being required for the purposes of applying prior art under 35 U.S.C. § 102 and § 103.
Regarding claim 8, the claim is indefinite because the claim recites “(as one monomer)” in parentheses in lines 2-3 and in line 4. It is unclear if the phrases in parentheses are limiting or merely exemplary of a possible configuration of the monomers that form the instantly claimed heterodimer construct, and accordingly, the metes and bounds of the claim cannot be readily determined.
If Applicant is intending to state that the instantly claimed heterodimer is formed from one monomer comprising the extracellular domain (ECD) of GluN1 or a fragment thereof and a second monomer comprising the ECD of at least one of the N-methyl-D-aspartate receptor (NMDAR) subunits GluN2A, GluN2B, GluN2C, or GluN2D, or a fragment thereof, it is suggested that the claim could be amended, e.g., to recite that “…the construct is a heterodimer formed from a first monomer comprising the ECD of GluN1 or a fragment thereof and a second monomer comprising the ECD of at least one of the NMDAR subunits GluN2A, GluN2B, GluN2C, or GluN2D, or a fragment thereof,” without parentheses.
Claim Rejections - 35 USC § 112(a)
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 1 and 3-8 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.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The claimed invention. The nature and scope of the claimed invention at issue is an NMDAR protein construct comprising one or more NMDAR autoantibody epitopes, wherein the construct comprises a fragment of an extracellular domain (ECD) of the NMDAR subunit GluN1 and a fragment of an ECD of at least one of the NMDAR subunits GluN2A, GluN2B, GluN2C, or GluN2D, wherein the protein construct lacks a NMDAR transmembrane domain, as set forth in claim 1 and its dependent claims. As provided by the state of the art (below), it is recognized in the field that a fragment of an NMDAR ECD may not necessarily contain NMDAR autoantibody epitopes unless, at minimum, the NMDAR ECD comprises the amino terminal domain (ATD) of the respective NMDAR subunit. Although claim 5 recites that the ECDs comprise or consist of the ATD of the respective GluN1/2 subunits, the claim also recites that the ECD may comprise “a fragment thereof”, which may or may not comprise the antigenic portion that serves as an NMDAR autoantibody epitope.
Furthermore, although dependent claims 3-4 broadly recite that the NMDAR protein construct comprises any of a broad genus of “dimerization domain” and/or “capture domain”, support in the disclosure is provided only for an antibody Fc domain.
State of the prior art. Gleichman (Journal of Neuroscience (2012) 32(32): 11082-11094) teaches that NMDARs are ionotropic glutamate receptors comprised of two GluN1 subunits and two GluN2/3 subunits (Introduction). Said GluN subunits contain two large extracellular domains: the amino terminal domain (ATD), which is further subdivided into two lobes, and the ligand binding domain, which is comprised of the S1 and S2 domains (Introduction). Gleichman discloses that in the autoimmune disorder anti-NMDAR encephalitis, patients produce autoantibodies to the GluN1 subunit of the NMDAR which crosslink the receptor and cause it to be internalized and destroyed (Introduction). Dalmau (The Lancet Neurology (2008) 7(12): 1091-1098) previously established that the epitope recognized by patients’ autoantibodies requires the amino (N-) terminal domain of the NR1 (GluN1) subunit. Dalmau showed that a protein comprising selective deletion of residues 25-380 of the NR1 subunit (“NR1d4”), which still assembles into a heteromer with NR2B (GluN2B), largely abrogates reactivity to patients’ autoantibodies (e.g., Results; web table 3, reproduced below). Dalmau also teaches that anti-NMDAR antibody reactivity was not modified by changing the NR2 subunit and retained by homomers of NR1 (e.g., Results; webtable 3). Gleichman (supra) further investigated the specific epitopes bound by patients’ anti-NMDAR autoantibodies by evaluating different GluN1 splice variants as well as variants of GluN2B (e.g., Results), and affirmed that presence of the GluN1 ATD is necessary and sufficient for anti-NMDAR autoantibody creation as evidenced by reactivity to the “ATD-TM4” GluN1 mutant comprising the GluN1 ATD and transmembrane domain (TM)4 (ATD-TM4) (e.g., Results; Figure 1). Gleichman further discloses that NR1 residues N368 and G369, which are located on the bottom lobe of the GluN1 ATD, bind to anti-NMDAR autoantibodies independently of GluN2 or GluN3A (e.g., Results; Figure 5).
PNG
media_image1.png
382
493
media_image1.png
Greyscale
As reviewed by Pleasure (Arch Neurol (2008) 65(5): 589-592), NMDAR autoantibodies against GluN2A and GluN2B (NR2A and NR2B) subunits have also been observed in, e.g., Rasmussen encephalitis, ischemic infarction and transient ischemic attack (TIA), and systemic lupus erythematosus (SLE) (e.g., Table 2). Huerta (Immunologic Research (2015) 63: 11-17) teaches that autoantibodies in neuropsychiatric SLE (NPSLE) recognize linear 5-residue epitopes having the amino acid sequence of “DWDYS” (residues 283-287) in GluN2A and “EWDYG” (residues 2884-288) in GluN2B, which are each localized in the extracellular, amino terminal domains of the respective subunits (page 12).
Scope of species disclosed in original specification. The Examples disclose the generation of soluble recombinant NMDA receptor Fc (srNR-Fc) fusion proteins, comprising the ATD of GluN1 with or without additional ECDs of GluN1, alone or combined with ECDs of the NDMAR subunits GluN2A or GluN2B, fused to the constant region of rabbit IgG1 heavy chain (rbFc) (page 106). Exemplary constructs are set forth in Table 3 (pages 106-107). Example 2 discloses that all of the srNR-Fc antigens were recognized by a recombinant human anti-NMDAR antibody (Figure 2). Per Example 3, Figure 3 summarizes the results of three ELISA experiments with a set of human sera from NMDAR encephalitis patients on the different srNR-Fc antigens, showing that “GluN1-ATD-Fc as well an antigens containing additional extracellular regions of GluN1 or GluN2 subunits yielded signals as in most of the NMDAR encephalitis patient sera, compared to Progranulin as a control” (pages 107-107).
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The written description requirement for a claimed genus may also be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. For each of the exemplary constructs of the invention (e.g., Table 3), all of the constructs comprise at minimum an ATD of the respective NMDAR subunits if not the full ECD (which, as disclosed by Gleichman (supra) above, comprises the ATD and the ligand binding domain). Exemplary constructs that do not comprise the ATD but retain the ability to react with anti-NMDAR antibodies are not disclosed in the present application. The disclosure also does not provide a showing that “a fragment of” an ATD of either GluN1/2 subunit is still recognized by anti-NMDAR antibodies, or what the structure of such a fragment may be. In addition, although the disclosure recites numerous exemplary dimerization domains (e.g., antibody Fc fragments, leucin-zipper domains, coiled coil domains; see page 14) and capture domains (e.g., antibody Fc fragments or protein tags such as a Myc-tag, HA-tag, HIS-tag or the like; see page 14), Applicant has only described NMDAR protein constructs comprising an antibody Fc fragment.
Conclusion. For the reasons presented above, one of skill in the art would not know which of the countless other NMDAR protein constructs encompassed by the highly general structural requirements of the claims would also comprise one or more NMDAR autoantibody epitopes. Given the limited number of species described and the fact that the species that were described cannot be considered representative of the broad genus, the Applicant did not possess the full genus of NMDAR protein constructs comprising one or more NMDAR autoantibody epitopes as broadly claimed at the time the application was filed.
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.
Claims 1 and 3-6 are rejected under 35 U.S.C. 103 as being unpatentable over Sharma (BMC Biotechnology (2018) 18:41) in view of Sansing (Nat Clin Prac Neurol (2007) 3(5): 291-296) and Vincent (US 2017/0153234 A1).
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 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 extracellular domain (or fragment thereof) of at least one of the NMDAR subunits GluN2A, GluN2B, GluN2C, or GluN2D.
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 NR2A and/or NR2B ECD, 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) 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.
Claims 1, 3-4, and 7-8 are rejected under 35 U.S.C. 103 as being obvious over Sharma (BMC Biotechnology (2018) 18:41) in view of Sansing (Nat Clin Prac Neurol (2007) 3(5): 291-296) and Vincent (US 2017/0153234 A1) as applied to claims 1 and 3-6 above, further in view of Egland (US 2015/0268241 A1).
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 a heterodimer of non-covalently bound monomers.
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 heterodimeric protein construct, which comprises an immunoglobulin Fc domain, for 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 conformal extracellular epitopes of NR1/NR2 heteromers for detecting anti-NMDAR autoantibodies. These conformal 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 conformal 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.
Citation of Pertinent Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure:
Passafaro (Nature Letters (2003) 424: 677-681) investigated the role of the extracellular domain of AMPA receptor subunit GluR2 on induction of dendritic spines. Passafaro generated soluble fusion proteins comprising an immunoglobulin constant region (Fc) fused to the N-terminal domain of GluR2 (“Fc-NTDR2”) or GluR1 (“Fc-NTDR1”) (e.g., Abstract; Methods; Results).
Czajkowsky (EMBO Mol Med (2012) 4(10): 1015-1028) reviews the applications of Fc-fusion proteins. Czajkowsky teaches that Fc-fusion proteins are composed of an immunoglobulin Fc domain directly linked to another peptide such as a receptor (e.g., Introduction; Figure 1; Table 1). Czajkowsky discloses, “From a biophysical perspective, the Fc domain folds independently and can improve the solubility and stability of the partner molecule both in vitro and in vivo, while from a technological viewpoint, the Fc region allows for easy cost‐effective purification by protein‐G/A affinity chromatography during manufacture. In addition, most Fc‐fusions are expressed as homodimers, and, as will be described later, can now be modified to polymerize into well‐defined complexes containing twelve fused partners (Fig 1C). Thus an increase in avidity, and with it potency, from an isolated fused partner is also a significant advantage of Fc‐fusion proteins” (Introduction).
Hinkkanen (US Patent No. 6,770,460 B1) describes a fusion protein having epitopes for at least two autoantigens selected from GAD65, IA2, and PPINS, wherein said epitopes are connected with a linker peptide, and wherein said fusion protein must be able to bind to a solid phase (e.g., Abstract; claims 1-5). Said fusion proteins comprise a 6xHis-tag “to enable antibody recognition and metal chelate chromatography purification and/or immobilization if necessary” (e.g., Figure 1; col 3-4). Hinkkanen further sets forth use of said fusion protein in an immunoassay for simultaneous detection of autoantibodies related to insulin-dependent diabetes mellitus (e.g., col 1-2).
Conclusion
No claims are allowed.
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, 9:00am - 5:30pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643