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 .
Status of Application, Amendments and/or Claims
1. Claims 1-20 are pending and under examination in the current office action.
Information Disclosure Statement
2. The information disclosure statements (IDSs) filed 11/24/2021, 03/24/2022, 05/15/2024, 08/26/2024, 05/12/2025 have been considered and the references therein are of record.
Claim Objections
3. Claim 18 is objected to because of the following informalities: the term hTau-p217” at line 6 of claim 18 is missing the “T” preceding residue 217 (i.e., “hTau-pT217”). Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
4. Claims 1, 6-18 and 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.
Claim 1 and dependent claims thereof are drawn to a method of detecting human Tau protein phosphorylated at threonine at residue 217 of SEQ ID NO: 1 (hTau-pT217) in a patient sample, comprising contacting the sample with an antibody that specifically binds to of hTau-pT217, and detecting binding of the antibody with hTau-pT217.
Dependent claims recite that the method further comprises contacting the sample with a second antibody, which antibody binds CNS-expressed isoforms of human tau, wherein the second antibody binds to an epitope region of human tau comprising glutamine at residue 124 and alanine at residue 125 of SEQ ID NO: 1. Independent claims 15 and 18 are drawn to a method of treating a neurodegenerative disease in a patient and a method of diagnosing a patient a having or at risk of having a neurodegenerative disease, respectively, wherein each method comprises contacting a patient sample with an antibody which specifically binds hTau-pT217. The claims are thus directed to methods comprising the use of a genus of antibodies defined entirely by function (i.e., binding to a particular epitope or isoform of tau) but with no defined structure.
The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
The factors to be considered when analyzing claims for compliance with the written description requirement include: actual reduction to practice; disclosure of drawings or structural chemical formulas; sufficient relevant identifying characteristics (e.g., disclosure of complete or partial structure, physical and/or chemical properties, structure/function correlation); method of making the claimed invention; level of skill and knowledge in the art; and predictability in the art. See MPEP §2163.
With respect to antibodies, the Federal Circuit has clarified Written Description as it applies to antibodies in the decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
The recitation of an antibody that specifically binds to hTau-pT217 or to hTau-E124A125, represent functional characteristics with no structure. While generically the structure of antibodies is known, the structure of the presently claimed antibodies can vary substantially within the above given claimed recitations. Thus, the genus is highly variant because a significant number of structural differences between genus members is permitted.
The instant specification teaches the production and amino acid sequences of only two monoclonal antibodies that bind hTau-pT217: a rabbit antibody called mAb A; and a chimeric antibody called mAb B having a rabbit variable region and a murine IgG constant region. Importantly, these antibodies have identical variable region sequences, which are the regions associated with antigen binding and specificity. The specification also provides one example of a murine monoclonal antibody that is specific for CNS-only expressed isoforms of human Tau, which antibody was raised against a peptide that includes glutamine at residue 124 and alanine at residue 125 of SEQ ID NO: 1 (called mAb C). Thus, at best the instant specification provides only one example each of a species of antibody that falls within each genus of functionally-recited antibodies of the claims (i.e., anti-hTau-pT217 antibodies and anti-hTau-E124A125 antibodies).
Accordingly, the instant application is lacking sufficient guidance on the structural attributes of an antibody that correlates to the functional requirements of the claimed invention. Regardless, the relevant art recognizes that diversity of antibodies binding to any particular target antigen or epitope is extremely broad, and therefore there is no way to reasonably predict the structure of the antigen-binding region of an antibody based upon the structure of an antigen or epitope alone (see, for example, Lloyd et al. Protein Eng. Design & Select, 2009, 22(3):159-168; and Edwards et al. J. Mol. Biol. 2003, 334:103-118). Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus nor guidance as to which of the myriad of molecules encompassed by the claimed antibodies would meet the limitations of the claims.
The limited examples of anti-hTau antibodies therefore do not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding or functional properties of the claimed antibodies. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen, 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions and which bound the target, but in no way allowed one to envisage the unique structure of a competitor’s (Centocor) antibodies which bound the same target but shared only 50% sequence similarity. Additionally, as noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted, emphasis in original). Therefore, those of skill in the art would not accept a disclosure of the lone anti-DUPAN-2 monoclonal antibody as evidence that the inventor had been in possession of the genus of functionally-recited antibodies presently claimed.
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. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014, Appeal No. 13-1338 at page 26). Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112(a).
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.
5. Claims 2-3, 16 and 19 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.
The claims recite that the claimed antibody comprises an LCDR2 of SEQ ID NO: 14 and an LCDR3 of SEQ ID NO: 15. According to the specification at p. 36 and the sequence listing, SEQ ID NO: 14 and 15 are the same sequence: LASSLSS. However, neither of the light chain variable region (LCVR) sequences of SEQ ID NOs: 5 or 8, nor the light chain (LC) sequences of SEQ ID NOs: 4 or 9 comprise a CDR3 that is LASSLSS (i.e., the instant SEQ ID NO: 15). Therefore, it appears that the sequence listed for the LCDR3 of the hTau-pT217 antibodies mAb A and mAb B is incorrect. The metes and bounds of these claims thus cannot be readily determined because the LCDR3 sequence has not been properly identified.
Claim Rejections - 35 USC § 102
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.
6. Claim(s) 1 and 13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yu et al. (J. Neurochem. 2009, 108:1480-1494).
Yu et al. teach a method that comprises detecting the level of tau-pT217 in brain tissue samples obtained from human patients (see “Animals and human brain tissue” at p. 1481, and Fig. 4 at p. 1487). The detection of pT217 levels was performed by Western blot analysis (see p. 1481 “Western blot analysis”), which method comprises contacting the patient samples with an antibody that specifically binds to pT217 of P-tau (see Table 1 at p. 1482) and detecting binding of the antibody. Such teachings anticipate the method of present claim 1.
Regarding claim 13, Yu demonstrates at Fig. 4 quantifying the levels of pT217 in human patient brain tissue samples from Alzheimer’s disease (AD) patients and age-matched normal human brain samples of control subjects.
7. Claim(s) 1, 6-7, 12-15 and 17-18 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Kolb et al. (US 2020/0408781 A1; filed Mar 4, 2019 and claiming priority to Mar 5, 2018).
Kolb et al. teach a method of detecting and measuring hTau-p217 (called p217+ tau by Kolb; see [0010] which identifies the epitope as pT217 of tau) in a biological sample comprising: contacting the sample with a capture antibody directed against a p217+ tau peptides, and contacting the captured p217+ tau peptides with a detection antibody directed against an epitope comprising amino acid residues 119-126, to thereby detect and measure an amount of p217+ peptides ([0012]). In particular, Kolb teaches that the term “p217+ tau” means a human tau protein or tau fragment that is phosphorylated at residue217 (pT217) of tau protein (see [0083]), and that a subject of the invention refers to a human ([0095]). Kolb further discloses the monoclonal antibody called pT3, which specifically binds p217+ tau peptides ([0089]). Accordingly, Kolb provides for all elements of the method of present claim 1.
Regarding claims 6-7, as stated above, Kolb indicates that the method of measuring p217+ tau in a subject sample comprises using the pT217 tau-specific antibody (pT3) as the capture antibody and an antibody that binds to an epitope comprising residues 119-126 of tau as the detection antibody. A monoclonal antibody called pT82 that is specific for the epitope comprising tau residues 119-126 is disclosed, for example, at [0030] and [0092]. This epitope comprises residues E124 and A125 of SEQ ID NO: 1, as in claim 7, and thus the pT82 antibody meets the limitation of a second antibody that binds an epitope region of human tau comprising residues 124 and 125 of SEQ ID NO: 1. Kolb further teaches that phosphorylated fragments of tau exist in, and are detectable in, the cerebrospinal fluid (CSF) (see [0006]-[0007]), and thus the methods of the invention provide for the detection of forms of tau in CSF that are linked to neurodegenerative disease ([0009]), which is on point to claim 6 reciting that the second antibody specifically binds CNS-expressed isoforms of human tau.
Regarding claim 12, Kolb teaches that the second antibody (i.e., the detection antibody) has a detectable label, such as various enzymes, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials ([0091]), all of which would provide for a detectable signal upon binding of the second antibody to the immune complex (i.e., capture antibody + hTau-pT217 + second antibody).
Regarding claims 13-14, Kolb demonstrates the quantification of p217+ tau peptides in patient CSF samples using the pT3xpT82 antibody pairing (see Example 7, [0259]-[0262]). Kolb also indicates that while CSF is preferred, biological samples can also include serum and plasma (see [0011]).
With respect to claim 15, Kolb teaches that the above discussed detection method further comprises administering to the subject an anti-p217+ tau antibody for treating or preventing a tauopathy in the subject (see [0020]).
Regarding claim 17, the tauopathy is disclosed to be Alzheimer’s disease (AD) ([0026]).
Finally, with respect to claim 18, Kolb teaches that the methods of the invention can be used for various diagnostic purposes, such as for diagnosing AD or other tauopathies in a subject or identifying a subject suitable for treatment with an anti-pT217+ tau antibody (see [0125]). In particular, the method comprises contacting a CSF sample from a subject with a capture antibody directed against p217+ tau peptides, contacting the captured p217+ tau peptides with a detection antibody directed against an epitope comprising residues 119-126 of tau protein to measure the amount of p217+ tau peptides in the sample, and determining whether or not the subject suffers from a tauopathy or is at risk of developing a tauopathy based on the measured amounts and/or ratios of the detected tau peptides (see [0130]).
Conclusion
8. Claims 1-3 and 6-20 are rejected.
9. Claims 4-5 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. The prior art does not teach or reasonably suggest an antibody which specifically binds hTau-pT217 and comprises the claimed LCVR-HCVR or LC-HC pairs. None of amino acid sequences SEQ ID NOs: 2-9 are taught or suggested by the prior art.
Advisory Information
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/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675