Do 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 .
Election/Restrictions
Claims 26-27, 29-32, and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected groups, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/05/2025.
Applicant’s election without traverse of Group 1, claims 1-3, 6, 8-9, 12, 16-19, 24, and 28 in the reply filed on 11/05/2025 is acknowledged.
Status of the Claims
Claims 1-3, 6, 8-9, 12, 16-19, 24, and 28 are pending and examined herein.
Priority
This application, filed 10/16/2022, is a 371 of PCT/EP2021/059759, filed 04/15/2020, and claims benefit of UNITED KINGDOM 2005564.6, filed 04/16/2020, and UNITED KINGDOM 2017987.5, filed 11/16/2020. This priority is acknowledged and the claims examined herein are treated as having an effective filing date of 04/15/2020.
Claim Objections
Claim 6 is objected to because of the following informalities: claim 6 recites “amino acid sequence KAGGFAPYYG-COOH (SEQ ID NO: 1)”; however, “COOH” is not part of SEQ ID NO: 1 as disclosed in the sequence listing. Appropriate correction is required.
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.
Claim 12 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 12 recites “…wherein the second monoclonal antibody is labeled, is linked to a fluorophore…” which is not proper English. This claim will be interpreted to mean “…wherein the second monoclonal antibody is linked to a fluorophore…”; however, appropriate correction is required.
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 1-3, 6, 8-9, 12, 16-19, 24, and 28 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.
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.
Further, to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include: a) the scope of the invention; b) actual reduction to practice; c) disclosure of drawings or structural chemical formulas; d) relevant identifying characteristics including complete structure, partial structure, physical and/or chemical properties, and structure/function correlation; e) method of making the claimed compounds; f) level of skill and knowledge in the art; and g) predictability in the art. See MPEP 2163.
Claim 1 recites “A monoclonal antibody that specifically recognises and binds to a
peptide having the C-terminus amino acid sequence KAGGFAPYYG”. Claim 3 recites that the monoclonal antibody not specifically recognize or bind to a peptide having the C-terminus amino acid sequence KAGGFAPYYGX, wherein X represents any amino acid.
The scope of the claims therefore covers the entire genus of monoclonal antibodies that recognize any peptide having the C-terminus amino acid sequence KAGGFAPYYG.
The specification describes a monoclonal antibody, NBH-242 (p. 26, para. 2, line 1), which binds to the claimed KAGGFAPYYG sequence, but not the elongated, truncated, or immunogenic peptide (p. 28, para. 3, lines 1-5). The specification discloses the heavy (p. 25) and light chain (p. 26) sequences of the antibody and identifies the CDRs, H1-3 and L1-3. The specification states that the antibody of the invention may comprise one or more of the H1-3 or L1-3 CDRs (p. 9, para. 3). Further, the specification states that the antibody of the invention has a light chain the comprises framework sequences identical or substantially similar to the sequences of NBH-242 (p. 9, para. 6). This description amounts to a full disclosure of the sequence of a single antibody capable of recognizing a peptide having the C-terminus amino acid sequence KAGGFAPYYG; however, the specification lacks sufficient variety of species to reflect the variance in the genus of monoclonal antibodies that recognize a peptide having the C-terminus amino acid sequence KAGGFAPYYG.
The specification describes art-recognized methods for preparing monoclonal antibodies (p. 8, para. 3). The described method produces many monoclonal antibodies, including those that do not have the claimed function, and need to be screened for the identification of their functions (p. 24, para. 3 and p. 25, para. 1).
The level of skill in the art is high, insofar as methods for making and/or screening monoclonal antibodies were well known in the art at the time of the invention. At the same time, however, as exemplified in the specification (p. 24-24, “Monoclonal antibody production and clone characterization”), it was not within the skill of the art to reliably predict whether a particular antibody would possess desired binding properties.
It was known that even small changes in antigen structure can profoundly affect antigen
binding interactions. For example, Harlow et al. (Harlow, E. and Lane, D., Antibodies: A Laboratory Manual (1988) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pages 23-26), who teach
that the loss of a single hydrogen bond can dramatically affect the ability of an antibody to recognize a cognate antigen (see especially page 26, first full paragraph). 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). Similarly, Colman et al. (Research in Immunology, 1994; 145(1): 33-36) teach that amino acid changes in an antigen can effectively abolish antibody antigen binding entirely (see entire document, particularly pages 33-34). Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how a one
amino acid change in the VHCDR2 of a particular antibody was tolerated whereas, the antibody
lost binding upon introduction of two amino changes in the same region.
Moreover, at the time of the invention, it was recognized that analysis of a given amino acid sequence only provides rough guides as to whether the sequence will bind to an antibody. See Lesniewski et al. (U.S. 6,596,476 B1) at column 5, lines 40-47, who further teach that there is no invariably predictable way to ensure whether a sequence has immunological activity short of preparing the sequence and testing it in an assay.
Trial-and-error screening would be necessary to test whether any given monoclonal antibody variant would be able to bind the claimed peptide. The need to conduct further studies to determine the identities of the members of the claimed genus indicates that Applicants were not in possession of the genus at the time of filing.
The importance of structure/function correlations was recently highlighted by the courts (Abbvie Deutschland v. Janssen Biotech and Ceniocor Biologics, App. No. 2013-1338, 1346 (Fed. Cir., July 1, 2014)). The Abbvie case involved antibodies and written description. The court stated: “We have held that “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.” Id. at 1350 (quoting Eli Lilly, 119 F.3d at 1568— 69).”. The courts then further stated: “With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus.” (emphasis added) and then state: " Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002). However, the record here does not indicate such an established correlation.
Rather, the specification as above suggests performing screening to determine whether monoclonal antibody variants would possess the requisite binding properties. While one could test a plurality of variants having different sequences to determine which, if any, have the requisite functional characteristics claimed, a “mere wish or plan” for obtaining the claimed invention is not adequate written description. See Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1566 (Fed. Cir. 1997); and Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). This gives rise to a situation in which the actual inventive work of producing at least a substantial number of the claimed variants would be left for subsequent inventors to complete.
For these reasons, the specification does not adequately describe the claimed genus of monoclonal antibodies that specifically recognize and bind to a peptide having the C-terminus amino acid sequence KAGGFAPYYG, and consequently, does not adequately describe the claimed methods of use or kits containing the monoclonal antibodies.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by “Enzyme-Linked Immunosorbent Assay Kit For Cross Linked C-Telopeptide Of Type III Collagen (CTXIII)” by Cloud-Clone Corp. (published July 2013, referred to herein as Cloud) as evidenced by NCBI “telo-propeptide of alpha 1 (III) procollagen, partial [Homo sapiens]” (referred to herein as NCBI, sequence information at https://www.ncbi.nlm.nih.gov/protein/CAA25878.1).
Regarding claim 1, Cloud teaches a monoclonal antibody specific for Cross Linked C-Telopeptide of Type III Collagen, i.e. CTXIII (p. 5, “TEST PRINCIPLE”, lines 1-2). This antibody is specific for a peptide, CTXIII, which has a C-terminal KAGGFAPYYG sequence, as evidenced by NCBI.
Claim 2 is considered a “Product-by-Process” claim (see MPEP 2113). Regarding product-by-process claims, "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (emphasis added). In this case, the claimed functional antibody would have the claimed function of recognizing and binding a peptide with the recited C-terminal sequence, regardless of the method by which it was made.
Claim 3 is 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 Cloud as evidenced by NCBI.
Regarding claim 3, Cloud teaches a monoclonal antibody specific for Cross Linked C-Telopeptide of Type III Collagen, i.e. CTXIII (p. 5, “TEST PRINCIPLE”, lines 1-2). This antibody is specific for a peptide, CTXIII, which has a C-terminal KAGGFAPYYG sequence, as evidenced by NCBI. Cloud teaches that the antibody has “excellent specificity” and that it exhibits “No significant cross-reactivity or interference between CTXIII and analogues” (p. 6, “SPECIFICITY”, lines 1-2). Based on this disclosure, it would be reasonable to assume that the disclosed antibody is specific for only the CTXIII peptide, i.e. it is unable to bind an elongated (SEQ ID NOs: 2 and 4) or a shortened version of the peptide (SEQ ID NO: 5). Thus, the monoclonal antibody specific for Cross Linked C-Telopeptide of Type III Collagen taught by Cloud anticipates or makes obvious instant claim 3.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 6, 8, 9, 12, 16, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over US 6,143,511 “SANDWICH IMMUNOASSAYS FOR COLLAGEN TYPE II DEGRADATION PRODUCTS” (published 11/07/2000, referred to herein as Eyre) in view of Cloud.
Regarding claim 6, Eyre teaches a method for detecting cross-linked type III collagen degradation peptides (para. 15, lines 17-21). Eyre teaches that this method can be used for type III telopeptides derived from the C-terminus (para. 15, lines 5-10). Eyre teaches that this assay comprises contacting the biological sample containing the target to a first monoclonal antibody and a second monoclonal antibody bound to the target and determining the amount of binding of the second monoclonal antibody (abstract, lines 1-10). Eyre teaches the use of “sandwich assays” using a target specific monoclonal antibody (para. 22, lines 1-2).
Regarding claim 8, Eyre teaches the assay is used to detect cross-linked CT-III (col. 15, lines 5-10).
Regarding claim 9, Eyre teaches that the biological sample is serum (col. 17, line 1).
Regarding claim 12, Eyre teaches that the second monoclonal antibody can be linked to a detectable marker, such as an enzyme (col. 11, lines 20-24).
Regarding claim 16, Eyre teaches that the bound second monoclonal antibody can be further bound by labeled antibody in order to determine the amount of binding of said second monoclonal antibody (col. 22, lines 54-60).
Regarding claim 28, Eyre teaches a kit for use in a sandwich assay comprising and first monoclonal antibody and second monoclonal antibody comprising a label (col. 11, lines 31-38).
However, Eyre does not specifically teach the use of or kit containing a monoclonal antibody bound to a surface specifically reactive with a sequence KAGGFAPYYG (claim 6).
Regarding claim 6, Cloud teaches an immunoassay for detecting cross-linked CT-III in a biological sample (p. 3 “ASSAY PROCEDURE”). Cloud teaches contacting the biological sample containing cross-linked CT-III (p. 3, Assay Procedure, step 1) with a first monoclonal antibody specific for the C-terminal epitope of CT-III comprising the amino acid sequence KAGGFAPYYG, as described above regarding claim 1 and incorporated herein, bound to a surface (p. 5, para. 1, lines 1-2).
Regarding claim 8, Cloud teaches that the immunoassay is used to quantify the amount of cross-linked CT-III (p. 5, para. 1, lines 5-7).
Regarding claim 9, Cloud teaches the antibody can be used with serum (p. 2, lines 1-6).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method and kit taught by Eyre by using the antibody taught by Cloud as the first and second monoclonal antibody. An artisan would have been motivated to make this modification because the detection of type III degradation can be useful to detect and monitor various inflammatory disorders, as taught by Eyre (col. 2, lines 61-67). An artisan would have a reasonable expectation of success because Eyre teaches that type III degradation can be measured by detecting crosslinked telopeptides (col. 1, lines 54-57) which is the intended purpose of the monoclonal antibody taught by Cloud.
Claims 17-19 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Eyre in view of Cloud as applied to claims 1, 6, and 8 above, and further in view of Haaften et al., “Misbalance in type III collagen formation/degradation as a novel serological biomarker for penetrating (Montreal B3) Crohn’s disease” Aliment Pharmacol Ther. (published 05/08/2017, referred to herein as Haaften).
The teachings of Eyre in view of Cloud, as described above regarding claims 8, are incorporated herein.
Regarding claim 17, Eyre teaches that the quantification cross-linked telopeptides of type III collagen could be used to detect and monitor disease states in humans (col. 2, lines 61-67). Eyre teaches that this assay is used to determine collagen type III degradation (col. 1, lines 34-38).
However, Eyre in view of cloud does not teach correlating the quantity of cross-linked CTIII with standard disease samples to evaluate severity of disease (claim 17), quantifying PRO-C3 and determining the ratio of CTX-III to PRO-C3 (claim 18), or correlating the ratio of CTX-III to PRO-C3 to standard samples to evaluate disease severity (claim 19) to the claimed list of diseases (claim 24).
Regarding claims 17-19 and 24, Haaften teaches measuring a type III degradation marker (“C3M”) and PRO-C3 (Table 1, p. 28, col. 1, para. 3, lines 1-5) and correlating the ratio of measured PRO-C3 to the measured degraded type III marker with standard Crohn’s disease samples to evaluate the severity of the disease (Figure 1B, “Type III collagen”, p. 32, col. 2, para. 1, lines 10-13).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the immunoassay to detect CTIII as taught by the combined teachings of Eyre and Cloud for the marker of type III degradation in the method for characterizing Crohn’s disease taught by Haaften. An artisan would be motivated to use the immunoassay for characterizing Crohn’s disease because, as taught by Eyre, measuring CTIII is an effective way to quantify type III degradation and, as taught by Haaften, type III degradation is affected in patients with Crohn’s disease. An artisan would have had a reasonable expectation of success in using this assay because immunoassays for detecting biomarkers is considered routine in the art of disease characterization and, as taught by Haaften, the measurement of biomarkers for type III degradation is useful in the characterization of Crohn’s.
Conclusion
No claims are allowable.
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/C.E./Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 February 4, 2026