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 .
Information Disclosure Statement
No IDS is disclosed. While a search and examination report is part of the file wrapper, references disclosed on the sear report should be submitted in this national stage application via an Information Disclosure Statement.
The listing of references in the PCT international search report is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, “the list ... must be submitted on a separate paper.” Therefore, the references cited in the international search report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all “statement” requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Priority
This application is filed on 07/25/2023. This application is a CIP of 16/968,277 filed on 08/07/2020, which is a 371 of PCT/EP2019/053003 filed on 02/07/2019. This application claims benefit of the foreign Application No. GB 1802070.1, filed on 02/08/2018.
Claim status
Claims 1-13 are pending and examining herein.
Specification
The disclosure is objected to because of the following informalities:
Par.16, missing Q after “SE” in “SE ID No: 1”;
Par.22, it lacks -[- before “0022]”.
Par.22, page 6, disclosed “a monoclonal antibody that that specifically bind to….” The word “that” is duplicated. Please delete one of them. The word “bind” should be read as -binds-.
Par.22, page 6, disclosed “N-terminus.” It appears that it should be a C-terminus instead of an “N-terminus” because “producing a monoclonal antibody that specifically binds to the N-terminus …” is not consistent with what is disclosed in the rest of the specification (see at least par.7, 11, par.22 lines 1-3). Either, no exemplary protocol for producing a monoclonal antibody that specifically binds to the N-terminus amino acid sequence LPGGYGLPYT (SEQ ID NO: 1) is found in the specification.
Appropriate correction is required.
Claim Objections
Claim 12 is objected to because of the following informalities: line 8, “an antibody biotinylation kit” should be in a separated line. 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.
Claims 4-8 and 12-13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 is unclear how to detect a fibrotic disease. The correlation of the amount of binding between said monoclonal antibody and peptides comprising said C-terminus amino acid sequence would not allow the person reading the claim in the absence of further information (e.g. the amount of binding between the antibody and peptides is higher or lower than the reference values) to decide if a fibrotic disease is present. It is also unclear how to quantify a fibrotic disease.
Claim 12, in the preamble, recites “an assay kit” while the subordinate limitations comprising three other kits (an antibody biotinylation kit, an antibody HRP labeling kit, an antibody radiolabeling kit). This makes the recitation of “an assay kit” confusing because there are kits within a kit but it is unclear what components are included in the biotinylation, antibody HRP labeling and radiolabeling kits.
All dependent claims are also rejected based on their dependency of the defective parent claims.
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 1-13 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.
Scope of the invention
Claims 1-10 recite a method of detecting or quantifying peptides having a C-terminus amino acid sequence LPGGYGLPYT by using a monoclonal antibody specifically reactive with a C-terminus amino acid sequence LPGGYGLPYT (SEQ ID NO: 1). Claim 11 recites a monoclonal antibody specifically reactive with a C-terminus amino acid sequence LPGGYGLPYT (SEQ ID NO: 1). Claims 12-13 recite a kit comprising a monoclonal antibody specifically reactive with a C-terminus amino acid sequence LPGGYGLPYT, wherein “the monoclonal antibody is raised against a synthetic peptide having the amino acid sequence LPGGYGLPYT (SEQ ID NO: 1)”.
The claimed antibody may be any of a genus of antibody where the antibody is defined only in terms of desired functions (e.g., desired binding properties) and not by structure or sequence. The claim scope is potentially enormous depending on how many of the products meet the functional requirements.
MPEP § 2163 states that written description requirement for a claimed genus may be satisfied through establishment of a structure-function correlation (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) or through a sufficient description of a representative number of species. Either is considered sufficient to show the applicant was in possession of the claimed genus.
“When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)) (emphasis added).
“[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” (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
In the present case, however, there is insufficient evidence of such an established structure-function correlation in the case of antibodies having the function of binding to an epitope having specific sequence ID No.1. Reciting that the antibodies are specific for an epitope within a given sequence only sets forth what the antibodies do and not what they are.
Regarding structure-function correlation, it is noted that one of skill in the art was aware that there is a lack of structure-function correlation in antibody molecules. Evidence of such in the form of publications in the art include the following.
First, the prior art recognizes that the full six CDR sequences are required to form the part of an antibody, i.e., the paratope, that specifically binds the target antigen. See Janeway et al. (Immunobiology: the Immune System in Health and Disease (2001), Elsevier Science Ltd/Garland Publishing, New York, NY, Fifth Edition, see sections 3-6 and 3-7) and Almagro et al. ("Humanization of Antibodies", Frontiers in Bioscience 13, 1619-1633, 2008) at introduction and section 4. While antibody CDRs are necessary for binding, they are highly diverse in structure, and their sequence does not correlate to binding in a predictable fashion.
The prior art also recognizes that a single protein can be bound by a very large and structurally diverse genus of antibodies (i.e., there is no common structural relationship even for antibodies that bind to the same protein, epitope, or overlapping epitopes). For example, Edwards et al. (2003, JMB 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines), and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well.
Lloyd et al. (2009, Protein Engineering, Eng. Design & Selection 22(3): 159-168) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding. Said reference further teaches that in their studies, of the 841 unselected and 5,044 selected antibodies sequenced, all but one of the 49 functional VH gene segments was observed, and that there are on average about 120 different antibodies generated per antigen. Said reference also teaches that a wide variety of VH and VL pairings further increase diversity. (See entire reference.)
Goel et al. (“Plasticity within the Antigen Combining Site May Manifest as Molecular Mimicry in the Humoral Immune Response”, The Journal of Immunology 173(12):7358-7367, 2004) made three antibodies that bind to the same 12-mer but have very different CDRs (see Figures 2-3 in particular).
Vajdos et al. (“Comprehensive functional maps of the antigen-binding site of an anti-ErbB2 antibody obtained with shotgun scanning mutagenesis” J Mol Biol. 2002 Jul 5;320(2):415-28, DOI: 10.1016/S0022-2836(02)00264-4) teach that amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (see especially at 416). Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen.
In view of the above, one cannot visualize or recognize the identities of the members of the genus that exhibit the claimed functional properties. Given the highly diverse nature of antibodies, and particularly the highly variable structure of antibodies in their CDR regions which are responsible for antigen binding, one cannot envision the structure of an antibody merely by knowing its binding characteristics.
Regarding a representative number of species, the instant specification fails to describe a representative number of species to provide adequate written description of the claimed genus as per MPEP § 2163. While the specification provides general descriptions of how to make antibodies that bind to a specific sequence ID No.1 and how to test them for desired binding (par. 48-51, and 60), only one species of antibody within the claimed genus is described with sufficient identifying characteristics using precise definitions such as structure, formula, chemical name, or physical properties such that one skilled in the art could visualize or recognize the identity of the claimed subject matter (par.51).
Moreover, Applicant’s attention is directed to the recent decision in Amgen Inc. v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The court discussed whether an antibody is adequately described by describing a newly characterized antigen. Specifically, the court referred to the decision in Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011). In that case, the patentee claimed a genus of antibodies containing a human variable region that has particularly desirable therapeutic properties: high affinity, neutralizing activity, and A2 specificity. Despite the fact that the specification disclosed human TNF-α protein, and despite the disclosure of the structures of more than one species of antibody related to the genus, the court ruled that the generic antibody claims at issue were invalid for lack of written description. Similarly, the instant claims recite a genus of antibodies that are specifically reactive with sequence ID No.1. Following the finding in Centocor, the instant claims are found to lack adequate written description.
Level of skill and knowledge in the art/predictability in the art
The level of skill in the art is high. In particular, methods for making and/or screening monoclonal antibodies with desired binding properties were well known in the art at the time of the invention. At the same time, however, it was not within the skill of the art to predict whether a given antibody would bind specifically to a particular epitope.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 4-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature and an abstract idea without significantly more.
Step 1 – Whether a claim is to a statutory category - YES
Claims 4-8 recite a method of immunoassay for detecting a fibrotic disease in a patient by determining the amount of peptides comprising a C-terminus amino acid sequence LPGGYGLPYT. Claims 9-10 recite a method for determining whether a patient is responding positively to a treatment for a fibrotic disease. The method comprises detecting the quantity of peptides comprising the C-terminus amino acid sequence LPGGYGLPYT at a first time point and at least one subsequent time point during the period of treatment. Therefore, the claimed inventions fall into one of the four statutory categories.
Step 2A Prong 1 – Whether the claim is directed to a judicial exception (i.e. Does the claim recite an abstract idea, law of nature, or natural phenomenon?) – YES
As explained in MPEP § 2106.04(II), a claim “recites” a judicial exception when the judicial exception is “set forth” or “described” in the claim.
Claim 4 recites determining the amount of peptides comprising said C-terminus amino acid sequence, and correlating said amount with a threshold.
Claim 9 recites determining the amount of peptides comprising said C-terminus amino acid sequence at a first time point and at least one subsequent time point during the period of treatment, then comparing the amount of the peptides among two or more time points.
The steps of “correlating” and “comparing” are abstract ideas, specifically, abstract mental process, which could be performed in the human mind, or by a human using pen and paper, insofar as it reads on comparing levels and drawing conclusions from this about whether the patient has a fibrotic disease or the patient responses positively to said treatment.
The “detecting … a fibrotic disease” in claim 4 and the “determining whether a patient is responding positively to a treatment for a fibrotic disease” can also be regarded as a law of nature, namely, the naturally occurring correlation between levels of peptides comprising said C-terminus amino acid sequence and the health condition, e.g., a fibrotic disease.
Thus, the claims 4-10 fall into judicial exception.
Step 2A Prong 2 - Does the claim recite additional elements that integrate the judicial exception into a practical application? NO
The Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception.
Claims 4-8 and 10 do not recite any additional element that integrate the exception into a practical application of the exception.
There is no subsequent step recited after the “detecting a fibrotic disease” step that would practically apply the method depending on the results of the measurements, e.g., treatment or other process steps that are performed after it is determined that the patient has a fibrotic disease. The treatment in claim 9 is not recited as an active step of the method, so the claims do not integrate the exception into a practical application of the exception.
Step 2B: Whether the additional elements contribute an “inventive concept”
In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP 2106.05.
Briefly, the claims 4-10 do not include additional elements that are sufficient to amount to significantly more than the judicial exception because of the following reasons.
Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, has been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
In claim 8, the Applicant defines what the biological sample is, but the biological sample does not add a meaningful limitation to the instant method as the biological sample would have been routinely used by those of ordinary skill in the art.
The method of using a monoclonal antibody to detect a biomarker in a sample of a patient for disease detection is well-understood, routine, and conventional. This position is supported by Leeming (US20150125964) and Parekh (US20170108511).
Leeming teaches a method for detecting a fibrotic disease by detecting fragments of a protein in a sample of a patient (see Abstract, par.14). The fragment of the protein is detected by using an antibody or a fragment thereof (e.g., a monoclonal or polyclonal antibody) having specific binding affinity for fragment (see par.15 and 26). The antibody or antibody fragment specifically binding peptide fragments of a protein such that for specific binding said fragments are required to have an antibody specific N-terminal or C-terminal amino acid sequence (see par.14 and 26).
Parekh teaches a method for detecting a fibrotic disease by detecting fragments of elastin in a urine sample of a patient (see par.27-28 and 33-34). The fragment of the elastin is detected by using an antibody or a fragment thereof (e.g., a monoclonal or polyclonal antibody) having specific binding affinity for fragment (see par.44).
Conclusion
Claims 1-13 are free of the prior art; however they are rejected under 35 U.S.C. 112 (a), (b) and 35 U.S.C. 101. The prior art of record does not suggest or make obvious a monoclonal antibody to peptides comprising the C-terminus amino acid sequence LPGGYGLPYT.
The closest prior arts are Dunker et al. (US20070105195), Leeming (US20150125964), Parekh (US20170108511) and Veidal et al. (US 9,404,932).
Dunker teaches an elastin peptide having an amino acid sequence LPGGYGLPYT (e.g., seq ID 143). Dunker does not teach an antibody to the peptide having the claimed sequence.
Leeming teaches a method for detecting a fibrotic disease by detecting fragments of elastin protein in a sample of a patient (see Abstract, par.14). The fragment of the protein is detected by using an antibody or a fragment thereof (e.g., a monoclonal or polyclonal antibody) having specific binding affinity for fragment comprising any one of the following C-terminal amino acid sequences, e.g., VLPGA-Citrulline, GGVAA-Citrulline (see par.15 and 25-26, Table 3). Leeming does not teach quantifying peptides having the claimed C-terminus amino acid sequence LPGGYGLPYT by using a monoclonal antibody to the claimed sequence.
Parekh teaches a method for detecting a fibrotic disease by detecting fragments of elastin in a urine sample of a patient (see par.27-28 and 33-34). The fragment of the elastin is detected by using an antibody or a fragment thereof (e.g., a monoclonal or polyclonal antibody) having specific binding affinity for fragment (see par.44). Parekh does not teach quantifying peptides having the claimed C-terminus amino acid sequence LPGGYGLPYT by using a monoclonal antibody to the claimed sequence.
Veidal teaches that method of diagnosis or of quantitation of pathological conditions comprise conducting an immunoassay to measure neo-epitope containing protein fragments naturally present in a biofluid sample (e.g., elastin), and associating an elevation of the measure in the patient above a normal level with the presence or extent of pathology (see Abstract). Veidal teaches using immunological binding partner reactive (e.g., a monoclonal antibody) with a C-terminal neo-epitope formed by cleavage of elastin (see at least Abstract, col.40-41 and 46; see tables 35-36 for the C-terminal neo-epitope formed by cleavage of elastin). Veidal does not teach quantifying peptides having the claimed C-terminus amino acid sequence LPGGYGLPYT by using a monoclonal antibody to the claimed sequence.
It lacks motivation for one having ordinary skill in the art to detect the claimed peptides comprising the C-terminus amino acid sequence LPGGYGLPYT.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHAU N.B. TRAN whose telephone number is (571)272-3663. The examiner can normally be reached Mon-Fri 8:30-6:30 CT.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy L Nguyen can be reached on 571-272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHAU N.B. TRAN/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 June 8, 2026
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