DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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 Claims
2. Applicant’s preliminary amendments received 08/17/2023 and 04/11/2024 are acknowledged.
3. Claims 1-23, 26-27, and 30-38 are pending in the instant application.
4. Applicant’s election of Group I, claims 1-7, 12-13, and 17, without traverse, is acknowledged, which is directed to an antibody or antigen-binding fragment thereof which binds 4R tau, and a pharmaceutical composition comprising the same.
5. Claims 8-11, 14-16, 18-23, 26-27, and 30-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
Information Disclosure Statement
6. The information disclosure statement (IDS) submitted on 04/11/2024 is acknowledged and the references cited therein have been considered.
Priority
7. The present application is a 371 National Stage Application of PCT International Application No. PCT/EP2022/053694, filed 02/15/2022, which claims the benefit of United Kingdom Patent Application No. GB2102227.2, filed 02/17/2021. Applicant' s claim for the benefit of prior-filed application is acknowledged.
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.
8. Claims 3, 6, 7, and 12 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.
(i) Claims 3, 6, 7, and 12 reciting “amino acid position X” are indefinite; it is indefinite to recite amino acids positions without structural features for the positions such as SEQ ID NOs. For example, the claimed 4R tau isoforms have 6 adult human tau isoforms arise form alternative splicing of exons 2, 3 and 10 of the MAPT gene, producing combinations of N-terminal inserts (0N, 1N, 2N) and C-terminal repeat domains (3R or 4R). It is not clear which isoform the claimed positions are directed.
(ii) the recitation “a peptide corresponding to a single epitope from the amino acid sequence encoding by exon 10 of tau” in claim 3(c) is indefinite because the word “corresponding” indicates analogous or equivalent to the claimed epitope, it is not clear what analog or equivalent epitope is being claimed.
(iii) The recitation “further comprises K298 and V300 of 4R tau protein” in claim 7 is ambiguous. Claim 7 depends from claim 2 which recite “4R tau protein isoforms”, it is not clear which 4R tau protein isoforms contain K298 and V300 and which 4R tau protein isoforms do not contain K298 and V300.
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.
9. Claims 1-7, 12-13, and 17 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 scope of the claim 1 encompasses a broad genus of tau-isoform-binding antibodies.
Claim 2 encompasses a subgenus of claim 1 that is specific to 4R tau protein isoforms.
Claim 3 encompasses a broad genus of anti-4R tau antibodies that binds to the amino acid region encoded by exon 10 of tau when the 4R tau protein contains a post translational modification at one or more of amino acid positions 279, 280, 281, 285 and 289 of Tau 4R, or amino acids 294 to 302 of 4R tau protein, or a peptide corresponding to a single epitope from the amino acid sequence encoded by exon 10 of tau or cross-blocks or is cross-blocked by any of the antibodies or fragment of (a) to (c).
Claims 6-7 encompasses a genus of anti-4R tau antibodies that binds amino acids K294, D295, N295 and I297 or further comprises K298 and V300 of 4R tau.
Claim 12 encompasses a genus of anti-4R tau antibodies that binds amino acids K294, D295, N296 and 1297, optionally where the epitope further comprises K298 and V300 of 4R tau protein.
Claim 13 is included because it is dependent on claim 1.
The scope of the claim 5 encompasses anti-4R tau isoforms antibodies with less than 6 intact CDRs as well as a subgenus of antibodies that encompass up to 5% variant in the VH and VL including CDRs; as well as cross-blocking antibodies (i.e., competing antibodies)
Claim 1, given broadest reasonable interpretation consistent with the specification, read on a genus of antibodies which bind tau isoforms. The claim fails to specify which specific tau isoforms are bound by each respective genus of antibodies. Moreover, the broadest claim (claim 1) does not indicate any specific structure for the antibodies nor does it indicate any specific antigen where the antibody would bind nor where upon it they would bind.
The USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018.
See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf.
The Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies, including the following.
“In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”.
In contrast to applicant’s reliance of describe the epitope of 4R tau isoforms in providing a fully characterized antigen / specific epitope as well as claiming structural elements of the antigen, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed anti-4R tau isoforms antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017).
There is no evidence that knowledge of the chemical structure of an antigen gives the required kind of structure identifying information about the corresponding antibodies Applicants attempt to describe the invention by describing something that is not the invention: viz., the antigens to which the antibodies may bind. There nothing in the disclosure that describes the antibodies as required by the test set forth in Ariad.
However, the anti-4R tau isoforms antibodies are required to practice the invention. The specification also fails to provide any specific structural or physical information so as to define a genus of antibodies having the desired therapeutic properties. Applicant is merely relying on the identification of 4R tau isoforms as the antigen and the well-known structure of antibodies in general. However, the claims do not recite a general antibody, but an antibody having a specific desired activity. However, Federal Circuit clarification of the law of written description as it applies to antibodies. Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017).
The claims are directed to a genus of anti-4R tau isoforms antibodies. However, Federal Circuit clarification of the law of written description as it applies to antibodies. The U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) 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 Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed anti-4R tau isoforms antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e. the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
Given the claimed broadly class of antibodies and in the absence of sufficient disclosure of relevant identifying characteristics for the broadly claimed class of antibodies to 4R tau isoforms, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014), MPEP 2163.
Claims 3 and 5 requires “cross-blocks or is cross-blocked by any of the antibodies” recited in claims 3a to 3c or 5a to 5c. While the amino acid sequence of 4R tau isofroms were known, immunizing an animal with 4R tau isofroms will generate antibodies directed to a number of different epitopes within the amino acid residues of 4R tau isofroms and not necessarily to the same epitope which is bound by the claimed antibody in claims 3 and 5 (a) to (c). The knowledge of the amino acid sequence of 4R tau isofroms, by itself, did not put Applicants in possession of antibodies that compete for binding with claimed anti-4R tau isofroms antibodies.
This case is thus similar to Centocor Ortho Biotech, Inc. v. Abbott Laboratories, 636 F.3d 1341 (Fed. Cir. 2011). In Centocor, patentee claimed an antibody or antibody fragment that competitively inhibits binding of A2 (a mouse antibody) and that binds an epitope of TNF-α with a specified affinity. 636 F.3d at 1346. Both TNF-α protein and antibodies to that protein were known in the literature. Id. at 1352. Patentee argued that the patent at issue satisfied the written description for the claimed antibodies because it "not only describes the antibodies by their binding affinity for TNF-α, but further describes the antibodies by specifying that they competitively inhibit binding of the A2 mouse antibody to TNF-α." Id. At 1349. The Federal Circuit rejected this argument, finding that "[a]t bottom, the asserted claims constitute a wish list of properties that a fully-human, therapeutic TNF-α antibody should have: high affinity, neutralizing activity, and the ability to bind in the same place as the mouse A2 antibody." Id. At 1351. The court explained that "[t]he specification at best describes a plan for making fully-human antibodies and then identifying those that satisfy the claim limitations."
In finding that the specification at issue did not provide written description support for the claimed antibodies, the Centocor court recognized that the written description does not require examples or an actual reduction to practice, but clarified that "it does demand ... that one of skill in the art can 'visualize or recognize' the claimed antibodies based on the specification's disclosure." Id. at 1353. "In other words the specification must demonstrate constructive possession." Id; see also, AbbVie Deutschland GmbH & Co., KG., v. Janssen Biotech, Inc., 759 F.3d 1285, 1301 (Fed. Cir. 2014) (reiterating requirement for structure-function correlation in functionally defined claims and finding that the patents at issue do not meet the written description requirement because they "do not describe any common structural features of the claimed antibodies.").
Here, as in Centocor, Applicant seeks to ground written description support for a claimed antibody in its competitive inhibition of another antibody (here, scFv VR7082, in Centocor, mouse A2 antibody) and in the description of a known antigen (here 4R tau isoforms, in Centocor, TNF-α). While the state of the art has progressed since the Federal Circuit's decision in Centocor, the basic problem remains that the description at issue must allow one of skill in the art to "visualize or recognize" the claimed antibodies. Here, the evidence of record does not support that the skilled artisan would have visualized or recognized the claimed antibodies based on the description provided. As in Centocor, the Specification provides only a plan for identifying the claimed antibodies.
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of anti-4R tau isoforms competing antibodies falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406.
Regarding the recitations of claim 5 - the specification provides one anti-4R tau antibody, VR7082, which was not random combinations of VH and VL i.e., it had specific VH domain (SEQ ID NO: 11, 13 and 15) paired with specific VL domain (SEQ ID NO: 3, 5, and 7, respectively). No other VH/VL domain was provided that mix the CDRs. The specification discloses only that single species within the instant claim scope. The instant application encompasses (but does not exemplify) fragments and CDRs modification up to 5% (deletion/addition/substitution) to the claimed HCDRs and LCDRs. There is no teaching identifying what amino acids can be varied within the VH-CDRs and/or VL-CDRs antibody regions and still retain antibody or fragments capable of binding the desired domain of 4R tau isoforms. Brown et al (J. Immuno. 1996 May, 3285-91 at 3290 and Tables 1 and 2) describes how a one amino acid change in the VH CDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region. Vajdos et al. (J. Mol. Biol. 2002, Jul 5, 320(2):415-28 at 416) 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. 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. The scope of the claims encompasses antibodies with VH or VL that encompass variation (addition, deletion, substitution) in their CDRs. The prior art discloses that 6 CDRs as being essential structure of antibody's binding site, and thus when intact, would provide enough structure to define the antibody's binding site (structure/function correlation) e.g., where amino acid substitutions can be made so as to change (e.g. 6CDR's) or retain (e.g., constant or variable framework) antigen binding. Neither the prior art nor applicant's disclosure defines sufficient representative antibodies and/or sufficient structure/function correlation between modifying the VLCDRs or VHCDRs regions of the disclosed antibody and the retention of a specific binding antibody that binds the 4R tau isoforms to satisfy the WD requirement for the claims.
The claim 5 also encompasses antibodies in which modification of the amino acids of SEQ ID NO: 17 may vary in either or both the VH CDRs and/or VL CDRs region via addition, deletion, substitution or insertion of one or more amino acids.
It is unlikely that antibodies or fragments thereof as defined by the claims which may contain less than the full complement of CDRs from the heavy and light chain variable regions of the VR7082 antibody fused to framework sequence, have the required binding function. The specification provides no direction or guidance regarding how to produce monoclonal antibodies as broadly defined by the claims. Undue experimentation would be required to produce the invention commensurate with the scope of the claims from the written disclosure alone. Further, the specification does not teach that a functional antibody can be obtained by replacing the CDR regions of an acceptor antibody with the less than all the 6 CDRs sequences of a donor antibody.
With respect to the recitation of an antibody which does not comprise all 6 CDRs of the antibody, the Examiner directs Applicant's attention to the training material given by Bennett Celsa, Example 2: (Ab genus: modified CDR's) slides 34-40. Example 2 of the Training material ((https://www.aipla.org/docs/default-source/committee-documents/bcp-files/2020/uspto-bcp-antibody-slides-final.pdf?sfvrsn=b377f2cc_0) which requires that the claims explicitly recite the binding antigen in addition to all 6 CDR regions for fulfillment of the written description requirements under § 112, 1. Slide 39 indicates that a claim encompasses antibodies with 6 intact CDRs as well as a subgenus of antibodies that encompass up to 10% variation (fragments and/or analogs) in the 6 CDRs lacks written description. Slide 40 provide the conclusion that, a single antibody species would not be deemed by one of skill in the art to be representative of a claim that defines an antibody that binds antigen X comprising at least 90% homology to the 6 CDR of the VH and VL chains.
Given the well-known high level of polymorphism of 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; 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 genus of antibodies encompassed in the claims at the time the instant application was filed.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
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.
10. Claims 1--7, 12-13, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2019/133799 (University of Florida Research Foundation, Pub date 07/04/2019, IDS Foreign Patent Ref #9).
Claim 1 is included because the ‘799 publication teaches an antibody or antigen-binding fragment thereof that: (a) specifically binds 4R tau protein isoforms in a physiological sample; or (b) specifically binds 3R tau protein isoforms in a physiological sample (see page 1 last paragraph to page 3 line 15).
Claim 2 is included because the ‘799 publication teaches an antibody or antigen-binding fragment thereof that specifically binds 4R tau protein isoforms (see page 1 last paragraph to page 3 line 15).
Claims 3, 6, 7, and 12 are included because the ’799 publication teaches an anti-4R tau antibody that binds to residues 275-305 (see page 2, paragraph 4). Given the high sequence identity/homology between the referenced/claimed polypeptides; the referenced antibodies would have the inherent property of binding the claimed 4R tau isoforms in the absence of objective evidence to the contrary.
Claim 4 is included because the ‘799 publication teaches (a) the antibody or antigen-binding fragment specifically binds 4R tau protein isoforms in cell lysates from cells expressing physiological 4R tau protein isoform(s), preferably in cell lysates from iPSC derived neuronal cells expressing 4R tau protein isoform(s); and/or (b) the antibody or antigen-binding fragment is able to detect 4R tau protein isoforms via immunofluorescence on, or in, cells expressing 4R tau protein isoform(s) (see page 1, last paragraph to page 3, line 15).
Claim 13 is included because the ‘799 publication teaches a SEQ ID NO: 37 which prevents the intrabody from being secreted by the ER (e.g. an antibody which is an intrabody) (see page 24 line 29 to page 25 line 9).
Claim 17 is included because the `799 publication teaches compositions comprising the antibodies which must including a pharmaceutical carrier or excipient (see page 34, lines 8+). Also, the `799 publication teaches that the primary antibodies diluted in 0.5% casein in TBS (i.e., carrier) (see page 33 under lmmunoblotting). Media (carrier) from the hybridomas were applied to plates (see page 32, under Hybridoma Screening).
Claim 5 is included because the reference antibody would cross-blocks or is cross-blocked by of the referenced antibodies in the absence of evidenced to the contrary.
The reference publication anticipates the claims of the instant application.
Conclusion
11. No claim is allowed
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALAN ALFANO whose telephone number is (571)272-3092. The examiner can normally be reached M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALAN ALFANO/ Examiner, Art Unit 1641
/MAHER M HADDAD/ Primary Examiner, Art Unit 1641
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