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 .
Priority
This application, Serial No. 17/701,779 was filed on 03/23/2022, and claims benefit under 35 U.S.C 119 to EP Application Serial No. EP21165011.4 filed on 03/25/2021.
Information Disclosure Statement
No new IDS has been entered for consideration.
Status of the claims
Claims 1-20 are pending.
Claims 1-2, 4, 7, 9, 13, and 20 have been amended.
Claims 2-5, 8-10, and 14-18 have been withdrawn from further consideration.
Claims 1, 6-7, 11-13, and 19-20 are under examination.
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 1, 6, 11, and 19 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 claim 1, it is unclear what method is used for detection of the autoantibodies, and there are no steps which describe how said detection is done.
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 13 and 20 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.
Claim 13 recites the use of an autoantibody in a buffered solution that binds to a polypeptide with the SEQ ID NO: 1 or a variant thereof, which solution is not a sample from a patient in need of a diagnosis. This antibody is not given any description in the specification other than it binds specifically to said polypeptide having the SEQ ID NO: 1 or a variant thereof, with no other structural information provided.
Claim 13 is drawn to a method using at least one buffered solution comprising the same antibody This antibody is not fully described the specification as originally filed.
The specification fails to provide any structure-function relationship of these antibodies, such as sequence description of the various CDRs. There is also no evidence in the disclosure that supports possession of antibodies that bind a polypeptide having 95% sequence identity to SEQ ID NO: 1, or sequence identities of more than 95% to SEQ ID NO: 1. The antibodies are not defined by any structure other than being antibodies that bind specifically to polypeptides having a sequence of SEQ ID NO: 1 or a variant thereof, wherein the variant comprises at least 95% sequence identity to SEQ ID NO: 1. In addition, there are no defined physical/and or chemical properties disclosed. There is no indication in the disclosure that Applicant purchased or fabricated the monoclonal antibody of claim 13, and the combination of characteristics of the invention as a whole, as described in examples in the specification, would not lead one of ordinary skill in the art to the conclusion that Applicant is in possession of a representative antibody which meets the functional characteristic as recited in claim 13, the Applicant only reciting the method uses an antibody which binds a with polypeptide having a sequence of SEQ ID NO: 1 or a variant thereof without showing possession of said antibody.
The specification does not identify a representative number of species to define the claimed genus, only that the non-specific antibody would have the ability to bind the target polypeptide. As such, this does not provide adequate written description for the claimed autoantibodies.
Regarding Applicant’s actual reduction to practice, the originally filed specification starting at pg. 6, line 23, discloses an autoantibody that binds to a polypeptide having the sequence SEQ ID NO: 1 or a variant thereof. Applicant claims autoantibodies binding a polypeptide having the sequence SEQ ID NO: 1 or a variant thereof are obtained by contacting a sample comprising the autoantibody with a polypeptide to promote the formation of a complex, wherein said autoantibody binds to said polypeptide; isolating the complex; and separating the autoantibody from the polypeptide. While there are steps used to obtain an autoantibody to a known polypeptide, there is no evidence that applicant is in possession of a representative number of species of the same autoantibodies such that written description of the entire genus is satisfied. Applicant has not shown possession of the antibody by sequence description of the CDRs or other structures and does not describe any other antibodies having the same binding function
Given the well-known high level of polymorphism of immunoglobulins / antibodies, the skilled artisan would not have been in possession of the vast repertoire of antibodies and the unlimited number of antibodies encompassed by the claimed invention, with up to 1015 different antibody specificities may be generated during B cell development and additional variety occurs antigenic influence on B cells (Abstract, Mix et al, Journal of Neurology, 2010). Considering this variety in antibody polymorphisms, there would be a correspondingly large number of unknown, undefined antibodies as there are polypeptides which would have at least a 95% sequence identity to SEQ ID NO: 1, one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genera of every antibody having the claimed function.
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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
The specification provides no such antibody structures that bind any of the polypeptides recited. The 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). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613. Furthermore, to satisfy the written description requirement for the genus antibody with specific epitope, Applicant must adequately describe representative antibodies to reflect the structural diversity of the claimed genus.
Claims 1, 6-7, 11-13, and 19-20 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.
Regarding the amendment to claims to recite the limitation of “wherein the variant comprises at least 95% sequence identity to SEQ ID NO: 1”, this limitation is new matter. The introduction of claim changes which involve narrowing the claims by introducing elements or limitations which are not supported by the as-filed disclosure is a violation of the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph. See, e.g., Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) (a "laundry list" disclosure of every possible moiety for every possible position does not constitute a written description of every species in a genus because it would not "reasonably lead" those skilled in the art to any particular species); and Regents of the Univ. of Minnesota v. Gilead Scis., Inc., 61 F.4th 1350, 1356-58, 2023 USQ2d 269 (Fed. Cir. 2023).
In the specification the Applicant provides a definition for a variant as a polypeptide or fragment thereof comprising amino acid sequences that are at least 40... preferably at least 99.315% identical to the reference amino acid sequence. This definition does not disclose the possession of these variants, only that when the word is used that all percentages between 40 and 99.315% would be considered within that term. This definition does not constitute a written description of every sequence with a percentage variation provided in the disclosure. This extremely wide range does not represent a particular species or even provide a reasonable limitation on the numbers of relevant species which may exist in polypeptides with said percent sequence identities. This definition does not enable any person skilled in the art to make use of these variants of polypeptides, and as such do not provide written description support of particular percentages used in the claims, making these amendments new matter as presented.
Maintained Rejections
Claim Rejections - 35 USC § 112, first paragraph
Claims 1, 6-7, 11-13 and 19-20 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. This is a written description rejection.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
The claims encompass large and variable genus of polypeptide components and variants, for example, see at claims 1, 7 and 13 “variant comprises at least 95% sequence identify to SEQ ID No. 1”. The claims require at least 95% identity with the indicated sequence, and functionally, the claims require that the polypeptide components be capable of binding to autoantibodies in sample.
Regarding Applicant’s actual reduction to practice, the originally filed specification at page 10, lines 13-25 or page 11, lines 18-30, etc. discloses many exemplary peptides. As presented, the claimed genus encompasses any sequence meeting the requirement as set forth above, including those sequences with mutations, additions or deletions.
Although the claims appear somewhat limited because the claims recite ‘at least 95% sequence identity” in reference to SEQ ID No. 1, the number of sequences comprising deletions/substitutions and/or additions of residues is actually enormous. Additionally, the specification at page 21, defines variant as fragments whose total lengths may be at least 6-1669 or more amino acids. With the aid of a computer, it may be possible to determine the amino acid sequences of the proteins that meet the structural requirements of the claims, it is not readily apparent from the claims or the specification, which of those sequences are also capable of binding to autoantibodies. While a definition of variant is given on pages 21-23, the specification does not provide a representative number of species such that one having ordinary skill can determine what position in the sequences can accommodate changes, and what other residues must necessarily be retained in order to maintain the claimed functional characteristics.
Regarding the knowledge in the art and the level of predictability, while the prior art does support some specific examples of a sequences that can accept modification such as Oh-hashi (e.g. Application of a novel HiBiT peptide tag for monitoring ATF4 protein expression in Neuro2a cells, Biochemistry and Biophysics Reports, Volume 12, 2017, Pages 40-45) discussing the five specific residues that can be replaced in the SmBit component of a NanoLuc system to form a HiBiT system with higher affinity,) the example in Oh-hashi is extremely specific. It is not predictable that any change in the sequence, while still maintaining 95% identity, can also maintain the recited functional characteristics. For example, regarding he SmBit sequence, it is not predictable that substitutions among the other residues that results in a peptide different from the HiBiT peptide could be accommodated and retain functional ability.
For example, regarding protein binding, Harlow & Lane, (Harlow, E and Lane, D., Antibodies: A Laboratory Manual (1988) Cold Spring Harbor Press, Cold Spring Harbor, NY, pages 23-26) discuss how even small changes in antigen structure can profoundly affect the strength of an antibody-antigen interaction. See entire selection, in particular page 26, first full paragraph. In particular, the loss of a single hydrogen bond can reduce the strength of interaction 1000-fold (ibid).
A noted above, the variability among the fragments encompassed by the claim is enormous and would encompass changes much more substantial than the loss of a single hydrogen bond or the mutation of a single amino acid; yet even such minor changes as these were known to dramatically affect function. Given the unpredictability associated with making even minor changes to antigen structure while preserving functional, with limited exception it is not possible to predict which, out of the enormous number of fragments encompassed by the claims, would be capable of still binding autoantibodies.
Along this same reasoning, see for example Lederman et al (A single amino acid substitution in a common African allele of the CD4 molecule ablates binding of the monoclonal antibody, OKT4. Mol Immunol. 1991 Nov;28(11):1171-81) found that a single amino acid substitution on the antigen CD4 ablated binding of a monoclonal antibody (see title and abstract). Lederman is further evidence that small substitutions (as small as a single residue) can change a protein binding event.
Although it is possible to envision the identities of those peptides/polypeptides that meet the structural requirements of the claims and exhibit at least 95% identify to the claimed sequences, it is not possible to discern from the data and examples provided in the specification, which of the countless possible species meeting the structural requirements, would also be capable of specifically binding autoantibodies in a sample. Given the unpredictability that is introduced by even a single residue substitution, short of testing each possibility, it would not be possible to distinguish those species encompassed by the claimed genus from those not encompassed. As a result, Applicant has not adequately described the claimed genus/genera of peptides/polypeptides having at least 95% identify with SEQ ID No. 1. The specification does not adequately convey evidence of possession of the entire invention a claimed.
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.
Claim 1, 7, 11, 12, and 19 are rejected under 35 U.S.C. 102(a) (1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Scott et al (Serum Autoantibodies Following Laser Induced Retinal Injury in Rabbits. Investigative Ophthalmology & Visual Science. April 2011, Vol.52, 2919. ARVO Annual Meeting Abstract, herein after Scott 1) in view of Scott et al (anti-Retinal Antibodies in Serum of Laser-Treated Rabbits. Biochemistry and Molecular Biology. Investigative Ophthalmology & Visual Science. April 2012. Vol. 53, No. 4: 1764-1771, herein after Scott 2) as evidenced by Germain-Lee et al (NVL: A New Member of the AAA Family of ATPases Localized to the Nucleus. Genomics. 1997; 44:22-34) and Sun et al (Valosin-Containing Protein, a Calcium-Associated ATPase Protein, in Endoplasmic Reticulum and Mitochondrial Function and Its Implications for Diseases. International Journal of Molecular Sciences. 2020, 21, 3842.)
Regarding Claim 1, Scott 1 discloses the detection of autoantibodies generated following retinal laser photocoagulations. Serum immunoreactivity to retinal proteins was determined using two-dimensional electrophoresis followed by western blot. Fifteen autoantibodies were detected in the serum of laser treated rabbits, one of which is valosin-containing protein (VCP). See entire meeting abstract.
Scott 1 differs from the instant claim in failing to specifically disclose the sequence of the proteins used is the test, i.e. SEQ ID No.1 nor does Scott 1 disclose the specifics of the assays to detect autoantibodies.
Scott 2 teaches the detection of autoantibodies following laser-induced retinal injuries. Scott 2 teaches retinal proteins were subjected to 2-D PAGE and transferred to PVDP membrane (page 1765, left column, 2-D PAGE and Western Blot). The membrane was then probed with sera (containing autoantibodies) from treated or control animals followed by HRP-conjugated secondary antibody (page 1765, paragraph bridging left and right column.) Scott 2 discloses candidate autoantigens identified in the studies includes Transitional endoplasmic reticulum ATPase (See page 1768, Table 1) which is Valosin-containing protein (See Sun, abstract).
While Scott 1 and 2 do not specifically disclose the sequence of VCP, this protein is recognized to be the same as a 110kDa nuclear protein designated NVLp (nuclear VCP-like protein) which has been sequenced and disclosed by Germain-Lee (see pages 24-25). This is the full-length 856 base pairs protein that is also disclosed by the instant specification as SEQ ID No. 1. See specification at pg. 34 under the heading SEQ ID NO: 1 [NVL-isoform1, Uniprot O15381-1].
Therefore, it would have been obvious to one of ordinary skill in the art at the time the application was filed that the methods disclosed by Scott 1 and 2, as evidenced by Sun and Germain-Lee, detect autoantibodies in a sample using VCP which is SEQ ID No. 1. A skilled artisan would have had a reasonable expectation of success in using the VCP taught by Scott to detect autoantibodies in a sample because Scott teaches the importance of detecting any autoimmune reactions after surgery in order to monitor injuries resulting from surgeries.
Regarding claim 11 and 19, Scott 2 teaches in the abstract the use of a sample comprising serum which was collected after laser-induced retinal injuries resulted in circulating anti-retinal antibodies that were detectable 3 months after the injury. This meets limitations in claim 11 wherein the sample is a bodily fluid comprising antibodies, and the limitations of claim 19 of the sample comprising serum.
Therefore, it would have been obvious to one of ordinary skill in the art at the time the application was filed that the methods disclosed by Scott 1 and 2, as evidenced by Sun and Germain-Lee above detect autoantibodies in a serum sample comprising antibodies to detect VCP for the reasons given above.
Regarding claim 12, Scott2 teaches Antibody binding was detected by immunofluorescence and visualized using an Olympus BX51 fluorescent microscope on pg. 1766, left column, 3rd paragraph. This meets limitations in claim 12 of using immunofluorescence to detect the antibodies.
Therefore, it would have been obvious, to a person of ordinary skill in the art,
before the effective filing date of the claimed invention, to detect VCP in a sample with immunofluorescence targeting autoantibodies as taught by Scott 2 while of Mattoon to diagnose a human of disease by using a blood sample from the human containing antibodies towards VCP. The person of ordinary skill in the art would have had a reasonable expectation of success using immunofluorescence techniques to detect the presence of antibodies in a serum sample because immunoassay using fluorescence labels is well known in the art.
Claims 6, 13, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Scott1, Scott2 as evidenced by Germain-Lee, and Sun as applied to claim 1 above, and further in view of Maejima et al (Biomedical Research, 2017) and Mattoon et al (WO2008064336A2 – previously cited) as evidenced by Andreasson et al (Frontiers in Neurology, 2015).
Scott1, Scott2, Germain-Lee, and Sun teach as above but fail to teach the sample from a patient having or suspected of having a systemic autoimmune disease or systemic sclerosis. Scott 1 or 2 teach the method of claim 13 where the binding between autoantibodies directed towards SEQ No. 1 is detected from a buffered sample.
Maejima teaches Valosin-containing protein as a possible sero-diagnostic marker of psoriatic arthritis, an autoimmune disorder. See Abstract.
Mattoon teaches biomarkers associated with autoimmune diseases, specifically Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE) and Anti-Neutrophil Cytoplasmic Antibody (ANCA) associated diseases, and methods, compositions and kits for the diagnosis. Regarding claim 6, Mattoon teaches in [0015] serum from patients diagnosed with RA, SLE and ANCA as well as healthy patients were profiled against a human protein microarray containing thousands of human proteins used as biomarkers for detecting one or more target antibodies in a test sample of an individual suspected of having an autoimmune disease, a method of diagnosing rheumatoid arthritis (RA) from a patient suspected of having the disease in and a method of diagnosing Systemic Lupus Erythematosus (SLE) from a patient suspected of having the disease (both systemic autoimmune rheumatic diseases) meeting limitations in claim 6. Mattoon discloses autoantigens associated with autoimmune diseases in Table 1, page 50. Specifically, Mattoon teaches VCP-like proteins as one possible antigen.
Therefore, it would have been obvious to a person of ordinary skill in the art
before the effective filing date of the claimed invention, to use the method of Scott 1 and 2 to detect autoantibodies to proteins such as VCP and to use the result to diagnose autoimmune diseases such as SARD or systemic sclerosis because Scott teaches VCP is diagnostic of autoimmune reactions and Maejima teaches serum level of VCP is a novel and useful diagnostic markers in patients with psoriasis arthritis (see Maejima page 445, left column.) Furthermore, a skilled artisan would have had a reasonable expectation of success in diagnosing SARD by detecting autoantibodies to VCP because Mattoon teaches the importance of diagnosing these conditions in a timely manner in order to monitor disease progression and provide appropriate treatment (see, Mattoon, paragraphs [0003] and [0048].)
Regarding claim 13, Scott 1, 2 & Maejima do not teach a method where the polypeptides as claimed is contacted with a buffered solution comprising antibodies specific to those peptides where the buffered solution is not a sample from a patient.
Mattoon is discussed above. Mattoon discloses a control mixture comprising autoantibodies to the autoimmune antigen (aka polypeptides) for use in their assay [0042], [00139] & [00146]. This control mixture meets the definition of “buffered solution” as defined by the instant specification on page 1, lines 20-23.
While Mattoon is silent with respect to the steps of the control assay, i.e. contacting polypeptide with control solution and detecting binding, Mattoon does specifically discuss the use of positive and negative controls, [00139] and [00146]; therefore, a skilled artisan would been motivated to perform the control assays using the control solutions as taught. As evidenced in Andreasson, where several validation and quality control methods designed for modification to fit desired procedures are discussed throughout the document, control validation assay necessitated contacting a capture reagent (i.e. polypeptide) with a positive control solution (i.e. buffered solution containing autoantibodies) and detecting results in order to create a reference. A skilled artisan would have been motivated to perform either positive or negative control assay in order to validate results from any assay. This meets the limitations in claim 13 of contacting a polypeptide of SEQ ID NO: 1 with a solution comprising an autoantibody in a buffered solution, the binding of which produces a signal which is then detected.
Therefore, it would have been obvious, to a person of ordinary skill in the art,
before the effective filing date of the claimed invention, to combine the teachings of Scott 2 and Mattoon as above and to include the use of controls in order to ensure proper operation of testing. The person of ordinary skill in the art would have had a reasonable expectation of success in using controls when running immunoassays.
Regarding claim 20, Scott 2 and Mattoon teach as above for claim 13. The use of a control by definition requires a known amount of reagent, or concentration of the antibody in this case, to properly validate a process, as evidenced in Andreasson. Mattoon further discloses antibody may be immunoglobulins or fragments thereof including those made by recombinant DNA methodologies, see [0058]. Mattoon discloses control validation assay in example 1 where multiple positive and negative control assays are performed, and anti-human IgG conjugated to AlexFluor is used to visualize the results. While Mattoon doesn’t specifically disclose a control solution comprising a mixture of two or more solutions comprising the antibody where each of the solution has a different concentration of the autoantibody, Mattoon does teach detecting the presence or level of biomarker and then compare this level with a reference range of the same biomarkers (i.e. autoantibodies) in order to determine the disease in paragraph [0051]. Using a ROC curve to plot the true positive rate, sensitivity, and false positive rate, specificity, to would allow for the monitoring of the performance of the assay in the determination of disease and allow for proper monitoring of control and validation procedures.
Scott 2 further discloses the detection of antibodies using a secondary antibody “anti-rabbit IgG-horseradish peroxidase (HRP)-conjugated secondary antibody” on pg. 1765, right column, first paragraph, which bind specifically to rabbit IgG antibodies Mattoon also teaches in [0107] examples of methods of detection of the binding of the target protein to an antibody, is the use of an anti-human lgG.
Therefore, it would have been obvious, to a person of ordinary skill in the art,
before the effective filing date of the claimed invention, to combine the teachings of Scott 2 and Mattoon as above to use recombinant antibodies for the well-known ability to create a stable, consistent product to use for controls and validations of assays. In addition, the creation of reference ranges requires the use of various concentrations of control substance to establish a curve and maintain proper assay results. The person of ordinary skill in the art would have been motivated to use secondary antibodies that bind to IgG to act as labeled, detectable controls to ensure control antibodies bind to analyte bound autoantibodies to be detected as an immunoassay control. The person of ordinary skill in the art would have had a reasonable expectation of success in using recombinant, anti-IgG antibodies as binding controls for an immunoassay.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Scott 1, Scott 2 as evidenced by Germain-Lee, and Sun as applied to claim 1 above, and further in view of Beach et al (US6001619).
Scott 1 and 2 teaches as above, and also teaches a method for isolating autoantibodies comprising a carrier having immobilized polypeptide (SEQ ID No.1), but fails to teach the subsequent dissociation, or separation of complexes to isolate the autoantibody.
Regarding claim 7, Scott 2 teaches as above and also teaches on pg. 1766, left column, 4th paragraph, immobilizing the target proteins a PVDF membrane overnight, then subsequently incubated with the primary antibody. Scott further teaches the isolation of the target complex through multiple washing steps to remove non-target complex material. This meets limitations in claim 7 of autoantibodies binding to an immobilized polypeptide which is then isolated.
Beach teaches ubiquitin ligases, and uses related thereto.
Beach teaches in col. 43, lines 60-62, the antibody can be replaced with another molecule able to bind one of either the regulatory protein or ubiquitin in a given embodiment. Beach teaches in col. 48, lines 12-34, “Typically, it will be desirable to immobilize either the regulatory protein … to facilitate separation of complexes from un-complexed forms of one of the proteins, as well as to accommodate automation of the assay. In an illustrative embodiment, a fusion protein can be provided which adds a domain that permits the protein to be bound to an insoluble matrix … which are then combined with the protein… and the test compound and incubated under conditions conducive to complex formation. Following incubation, the beads are washed to remove any unbound protein…the complexes can be dissociated from the matrix, separated by SDS-PAGE gel, and the level of, for example, pub protein found in the matrix-bound fraction quantitated from the gel using standard electrophoretic techniques. This separation would also separate the binding proteins, which were changed out for antibodies, but would function and separate out the same as antibodies.
It would have been obvious to one having ordinary skill in the art at the time the invention was made to capture the autoantibodies as taught by Scott 1 & 2, and use the method taught by Beach to dissociate, separate and isolate the autoantibody in order to perform further analysis and/or use them as reagents in control solutions, for example. One having ordinary skill in the art would have been motivated to use the technique taught by Beach to dissociate and isolate the autoantibodies captured using the method of Scott 1 & 2 because the abilities to capture and isolates proteins from a complex sample is well known in the art as taught by Beach.
Response to Arguments
Applicant Arguments - Anticipation
Applicant's arguments filed 08/22/2025 regarding the anticipation or obviousness of claim 1 have been fully considered but they are not persuasive.
Regarding the arguments for the “Anticipation Rejection”, Applicant argues that an autoantibody that specifically binds to a polypeptide having 95% sequence identity with SEQ ID NO: 1 is not disclosed, taught, or suggested by the prior art. Applicant argues Scott 1 only discloses the detection of autoantibodies against a polypeptide generically termed "valosin-containing protein" (VCP), and Scott 2 to suggest it discloses candidate autoantigens including a Transitional endoplasmic reticulum ATPase which is Valosin-containing protein (VCP) (from abstract of Sun), which in turn is the VCP-like protein in Germain-Lee and has the same 856 base pairs as SEQ ID NO. 1 (present specification p. 34, NVL-isoform 1, Uniprot 015381-1). However, Applicant notes that Scott 2 at p. 1768, Table 1 of autoantigens, lists the Uniprot accession no. "P03974”.
The Uniprot accession no. P03974 relates to the ATPase disclosed in Scott 2), and has a different 806 amino acid sequence in Uniprot beginning "MASGADSKGD..." and ending with "DLYG". A BLAST sequence comparison shows there is only about 70 % sequence identity between these two sequences rather than the presently claimed at least 95 % of amended claim 1.
Applicant argues there is no motivation to change the sequence of Scott 2 to the sequence disclosed in Germain-Lee, and no disclosure of the Germain-Lee sequence as acting as an autoantigen, nor that it could be bound by autoantibodies in a sample, as presently claimed. The Office is using hindsight in combining references, and one of ordinary skill in the art would not arrive at present amended claim 1.
Examiner Response - Anticipation
In response to Applicants argument that “an autoantibody that specifically binds to a polypeptide having at least 95% sequence identity with SEQ ID NO: 1 is not disclosed, taught, or suggested by the prior art.”, at least 95% sequence identity is only one alternative limitation in claim 1, the other, and one which is met by the prior art is a polypeptide having the same sequence identity as SEQ ID NO: 1.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In this case, the additional sources are evidentiary to show that the autoantibodies detected in the primary reference are directed to the same autoantigens as those having the sequence of SEQ ID NO: 1. There are many synonyms for the same polypeptide as disclosed in the prior art, and Germain-Lee shows a full 856 amino acid sequence directed towards this polypeptide which would bind to one of the autoantibodies detected in the primary Scott 1 reference.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case evidentiary references that are necessary to identify the correct sequence for the claimed polypeptide due to the number of synonyms the polypeptide are referred to as the prior art and the method taught by the Scott references.
Scott 2 was only used to identify a synonym for the polypeptide, and not to identify the sequence itself, it is not necessary to identify the specific sequence used in Scott 2 as it is not the sequence from Scott 2 that is being used for the rejection, only the identification of a polypeptide named with a synonym for the polypeptide with the sequence of SEQ ID NO: 1, which while is not addressed by the Applicants argument that the prior art does not teach 95% sequence identity with SEQ ID NO: 1, this teaching is not necessary to meet the other limitation of claim 1 of a polypeptide having the sequence of SEQ ID NO: 1. The motivation to change the sequence is not needed because there is no changing of a sequence, only the identification of the proper sequence for the polypeptide the autoantibody from Scott 1 is directed against. When identifying autoantibodies directed towards a polypeptide having the sequence of SEQ ID NO: 1, the autoantigen sequence identified in Germain-Lee has the name of the synonym of a polypeptide identified by autoantibodies in Scott 1.
Applicant's arguments do not comply with 37 CFR 1.111(c) because they do not clearly point out the patentable novelty which he or she thinks the claims present in view of the state of the art disclosed by the references cited or the objections made. Further, they do not show how the amendments avoid such references or objections. The amendments for variants with 95% sequence identity to SEQ ID NO:1 does not rule out the polypeptide with a sequence identity of 100% of SEQ ID NO:1, which is the alternative recited limitation in claim 1, disclosed in Germain-Lee. Applicant has argued that the combination of sources is not obvious, but the combination of sources shows anticipation of claim 1 through the primary reference and evidentiary references. As such, detecting, in a sample, an autoantibody that specifically binds to a polypeptide sequence consisting of SEQ ID NO: 1, has been anticipated by the cited references. Also, there is no additional reasoning as to why claims 7, 11-13, and 19 would be novel except to say they depend from claim 1. Therefore, the arguments are found to be non-persuasive and the rejections are maintained.
Applicant Arguments – Obviousness
Applicant's arguments filed 08/22/2025 regarding the obviousness of claim 1 have been fully considered but they are not persuasive. Applicant argues that claims 6-7, 13, and 20 would not be obvious because they do not contribute anything which would overcome the lack of anticipation or obviousness of claim 1.
Examiner Response - Obviousness
Because no additional reasoning was given as to why these claims should not be rejected except for their dependence on claim 1, therefore, these arguments are also found to be non-persuasive and the rejections are maintained.
Applicant Arguments – Written Description
Applicant's arguments filed 08/22/2025 regarding the Written Description rejection of claims 1, 6-7, 11-13, and 19-20 have been fully considered but they are not persuasive. Applicant argues the reduction in variation is supported by p. 22, 11. 12-15 of the specification as filed, in exchange for protection of the many embodiments of polypeptide sequences falling within the claimed scope and fully described such as at p. 10, 11. 13-25 and p. 11, 11. 18-30.
Examiner Response – Written Description
Examiner does not find Applicants arguments persuasive. The reduction in variation referred to in the specification refers to various percentages of variation that may be used for determination of sequence identity and do not provide limited, specific examples of variants to the polypeptide that are known to work for the claimed method. In addition, the amended variation from 80% to 95% still leaves room for approx. 43 non-specific amino acid substitutions in the amino acids of the polypeptide, and the following based on the previous OA still applies when changed from 80% to 95%. In addition, there is no disclosure in the specification of possession of polypeptides other than those with the sequences disclosed. Possession of variants of the polypeptides with the disclosed sequences is not evident in the specification, only polypeptides specifically with the disclosed sequences, including SEQ ID NO: 1.
Therefore, the Written Description rejection is maintained in spite of amendments.
Withdrawn Rejections
Applicant Arguments and Amendment – Indefiniteness
Applicant’s arguments and amendments regarding the 112(b) Indefiniteness, filed 08/22/2025, with respect to Claim 20 have been fully considered and are persuasive. The 112(b) Indefiniteness rejection of claim 20 has been withdrawn.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JIM ATWELL, D.Sc., M.S., MLS whose telephone number is (571)272-0890. The examiner can normally be reached Generally Mon-Thurs: 7:30-5:00 EST and every other Fri: 7:30-4:00 EST.
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/JIM ATWELL/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 September 30, 2025
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