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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/13/2026 has been entered.
Status of the Claims
Claims 8 – 9, 18 – 21, 26, 43, 98 – 105, 107 – 109, and 111 were pending with claims 9 and 19 withdrawn from consideration. Claims 8, 21, 26 have been amended. Claims 8, 18, 20 – 21, 26, 43, 98 – 105, 107 – 109, and 111 are the subject of this Office Action.
Claim Objections
Previous objection, withdrawn: claim 8 is objected to because of informalities.
In view of the amendment to claim 8 in the reply of 12/08/2025, this rejection is withdrawn.
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.
Claims 8, 18, 20 – 21, 26, 43, 98 – 105, 107 – 109, and 111 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.
At the time the invention was made, the art teaches that there is an interest in optimizing natural properties (affinity, specificity, stability, solubility, and effector function) in antibodies. A common challenge during antibody optimization is that improvements in one property (e.g. affinity) can lead to deficits in other properties (e.g. stability) See RABIA (Rabia LA, et al. Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility. Biochem Eng J. 2018 Sep 15;137:365-374; see PTO-892: Notice of References Cited), abstract. RABIA teaches that the most important antibody properties are mediated by their complementary-determining regions (CDRs) within the variable heavy and light regions. See RABIA, Introduction.
The claims are drawn to amino acid changes. Claim 8 indicates changes in 4 amino acids of the heavy chain of SEQ ID NO: 127 of part a and 9 amino acids in SEQ ID NO: 129 in part b. The spec identifies this antibody as 9F5. Below, the CDRs are underlined and the dots above the sequences represent every 10th amino acid. The required mutations in the amino acids are indicated in bold.
SEQ ID NO: 127 (heavy)
EVQLVQSGAEVKKPGATVKISCKASGFNIKDDYMNWVQQRPGKGLEWIGWIDPENGDTEYASKFQGRATMTADTSTNTAYMELSSLRSEDTAVYYCTTSNGWGQGTLVTVSS
SEQ ID NO: 149 (light)
DIQMTQSPFSLPVTPGESASISCRSSKSLDHSNGITYLYWYGQKPGQSPQLLIYQGSNRASGVPNRFSSSGSGTDFTLKISRVEAEDVGVYYCAQNIELPLTFGQGTKLEIK
Given RABIA’s teaching that mutations can affect the function of the antibody, the mutations in SEQ ID NO: 127 and 149 are compared to the sequences of 9F5 and mutants of 9F5 in Figures 1 and 2 to see what amino acid residues can be changed and still result in an antibody that binds to tau. Regarding the heavy variable region, there is support in claim 8a for N, I, N, D at residues 28, 51, 55, and 57 (mouse 9F5), but no support for any combination of the mutations, such as N, V, N, E, at residues 28, 51, 55, and 57. Given RABIA, one cannot predict that any combination of amino acid changes in the CDRs would result in one that binds tau.
Regarding the light chain, the specification does not teach that all residues in claim 8b were shown to result in an antibody that binds tau. For example, amino acid 29 has support for L, but does not have support for D, T, Q. Amino acid 30 has support for L and D but not for G, S, E, T, N, A, P, or I. Also, it is noted that for optional additional mutations, the specification does not provide guidance for the substitutions. For example, amino acid 80 in the heavy variable domain has been shown to be Y in all mutants. However, the claim indicates that the residue can be Y, Q, D, N, or G. There is no support for Q, D, N, or G.
Claim 8 is written such that any heavy variable region in a) can be paired with any light variable region in b). For example, the claim is written as though hu9F5VHv1 can be paired with hu9F5LHv6. However, given RABIA there is no support for these antibodies.
In addition to the antibodies binding to tau, they also must be inhibitory or function to reduce aggregation as required by claim 107. Regarding aggregation, the specification teaches that the original mouse antibody 9F5 can identify tau aggregates (Example 16), that combinations of mutations in the antibody contribute to the lack of antibody aggregation (Example 17) that some mutations contribute to the antibody being resistant to low pH (Example 18), and that antibodies were tested for aggregation in PEG (Example 19), the specification does not teach any assay where the antibody blocks aggregation of tau. In this respect, none of the antibodies in claim 8 appear to address claim 107.
Thus, based on the teachings of RABIA regarding the lack of predictability in the art, one having ordinary skill would conclude that the Applicant was not in possession of the claimed genus of antibodies or antigen-binding antibody fragments that specifically bind to tau having the claimed mutations as recited in the present claims.
Claims 8, 18, 20 – 21, 26, 43, 98 – 105, 107 – 109, and 111 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 enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Scope of Enablement
Claims 8, 18, 20 – 21, 26, 43, 98 – 105, 107 – 109, and 111 are rejected under 35 U.S.C. 112(a) because the claims recite an antibody or antigen-binding antibody fragment that specifically binds to tau comprising: (a) a mature heavy chain variable region comprising SEQ ID NO: 127 and a mature light chain variable region comprising SEQ ID NO: 149 with considerable variations in the CDRs. Because the CDRs confer specificity and function to an antibody or antigen-binding antibody fragment that specifically binds to tau as claimed, an antibody or antigen-binding antibody fragment with significant variations at the CDRs may not function as intended.
In this regard, the application disclosure and claims have been compared per the factors indicated in the decision In re Wands, 8 USPQ 2d 1400 (Fed. Cir., 1988) as to undue experimentation. The factors include:
1) the nature of the invention;2) the scope or breadth of the claims;3) the state of the prior art;4) the predictability or unpredictability of the art; 5) the relative skill of those skilled in the art; 6) the presence or absence of working examples; 7) the amount of direction or guidance presented and,8) the quantity of experimentation necessary.
The relevant factors are addressed below on the basis of comparison of the disclosure, the claims and the state of the prior art in the assessment of undue experimentation.
Scope or breadth of the claims: Present independent claim 8 and dependent claims thereon recite:
8. A antibody or antigen-binding antibody fragment that specifically binds to tau comprising: (a) a mature heavy chain variable region comprising SEQ ID NO: 127, except that amino acid position 28 of SEQ ID NO: 127 is occupied by N or T, amino acid position 51 of SEQ ID NO: 127 is occupied by I or V, amino acid position 55 of SEQ ID NO: 127 is occupied by N or D, and amino acid position 57 of SEQ ID NO: 127 is occupied by D or E; optionally, wherein at least one of: amino acid position 1 of SEQ ID NO: 127 is occupied by Q or E, amino acid position 5 of SEQ ID NO: 127 is occupied by Q or V, amino acid position 11 of SEQ ID NO: 127 is occupied by L or V, amino acid position 12 of SEQ ID NO: 127 is occupied by V or K, amino acid position 17 of SEQ ID NO: 127 is occupied by S or T, amino acid position 20 of SEQ ID NO: 127 is occupied by L or I, amino acid position 23 of SEQ ID NO: 127 is occupied by T or K, amino acid position 38 of SEQ ID NO: 127 is occupied by K, R, or Q, amino acid position 40 of SEQ ID NO: 127 is occupied by R or A, amino acid position 42 of SEQ ID NO: 127 is occupied by E or G, amino acid position 43 of SEQ ID NO: 127 is occupied by Q or K, amino acid position 48 of SEQ ID NO: 127 is occupied by I or M, amino acid position 67 of SEQ ID NO: 127 is occupied by K or R, amino acid position 70 of SEQ ID NO: 127 is occupied by I or M, amino acid position 76 of SEQ ID NO: 127 is occupied by S or T, amino acid position 77 of SEQ ID NO: 127 is occupied by N or D, amino acid position 80 of SEQ ID NO: 127 is occupied by Y, Q, D, N, or G, amino acid position 81 of SEQ ID NO: 127 is occupied by L, M, P, D, G, or E, amino acid position 82 of SEQ ID NO: 127 is occupied by Q or E, amino acid position 83 of SEQ ID NO: 127 is occupied by L, P, K, R, E, or N, amino acid position 84 of SEQ ID NO: 127 is occupied by S or G, amino acid position 86 of SEQ ID NO:127 is occupied by L, G, D, or S, amino acid position 87 of SEQ ID NO: 127 is occupied by T or R, amino acid position 97 of SEQ ID NO: 127 is occupied by A or T, amino acid position 98 of SEQ ID NO: 127 is occupied by S or T, amino acid position 107 of SEQ ID NO: 127 is occupied by T or L, and amino acid position 108 of SEQ ID NO: 127 is occupied by L or V and
(b)_a mature light chain variable region comprising SEQ ID NO: 149, except that amino acid position 29 of SEQ ID NO: 149 is occupied by L, D, T, or Q, amino acid position 30 of SEQ ID NO: 149 is occupied by L, D, G, S, E, T, N, A, P, or I,amino acid position 35 of SEQ ID NO: 149 is occupied by I, Y, E, K, G, or Q, amino acid position 36 of SEQ ID NO: 149 is occupied by T, N, or G, amino acid position 38 of SEQ ID NO: 149 is occupied by L, N, T, S, R, or G, amino acid position 56 of SEQ ID NO: 149 is occupied by M, G, E, D, K, or I, amino acid position 59 of SEQ ID NO: 149 is occupied by L, R, G, or T, amino acid position 94 of SEQ ID NO: 149 is occupied by A or G, amino acid position 97 of SEQ ID NO: 149 is occupied by L, D, E, G, Q, T, or I, and amino acid position 98 of SEQ ID NO: 149 is occupied by E or G. optionally, wherein at least one of: amino acid position 3 of SEQ ID NO: 149 is V or Q, amino acid position 7 of SEQ ID NO: 149 is A or S, amino acid position 8 of SEQ ID NO: 149 is A or P, amino acid position 9 of SEQ ID NO: 149 is F or L, amino acid position 11 of SEQ ID NO: 149 is N or L, amino acid position 15 of SEQ ID NO: 149 is L or P, amino acid position 17 of SEQ ID NO: 149 is T or E, amino acid position 18 of SEQ ID NO: 149 is S or P, amino acid position 42 of SEQ ID NO: 149 is L, Q, G, or I, amino acid position 44 of SEQ ID NO: 149 is R or K, amino acid position 65 of SEQ ID NO: 149 is N or D, amino acid position 69 of SEQ ID NO: 149 is G or S, amino acid position 71 of SEQ ID NO: 149 is E or G, amino acid position 78 of SEQ ID NO: 149 is L, P, or G, amino acid position 79 of SEQ ID NO: 149 is R or K, amino acid position 80 of SEQ ID NO: 149 is I, D, P, Q, or G, amino acid position 81 of SEQ ID NO:149 is S, P, or G, amino acid position 82 of SEQ ID NO: 149 is R or D, amino acid position 83 of SEQ ID NO: 149 is V, R, D, E, P, K, G, or Q, amino acid position 90 of SEQ ID NO: 149 is V or G, amino acid position 91 of SEQ ID NO: 149 is Y or T, and amino acid position 105 of SEQID NO: 149 is G or Q.
Degree of predictability or unpredictability in the art: As taught by RABIA, given that the maximal chemical diversity of antibody CDRs is unimaginably large (>1078 antibody variants based on 20 different amino acids at ~60 sites in the CDRs), it is extremely challenging to define the sequence determinants of antibody specificity (see 3. Antibody affinity/specificity trade-offs, second paragraph, p.4). Thus, the level of unpredictability in the art is high, especially since the claims results in CDRs that vary greatly from the antibodies presented in the present specification.
Relative skill possessed by those in the art: In view of the state and complexity of the prior art, and the scope of the claims, which are drawn to an antibody or antigen-binding antibody fragment that specifically binds to tau, the level of skill in the art is high and is at least that of a medical doctor or Ph.D. scientist with several years of experience in the fields of antibody or antibody engineering and/or immunotherapy.
Presence or absence of working examples: The specification does not provide examples that define the effects resulting from all the possible alterations of the CDRs of the claimed antibody or antigen-binding antibody fragment that specifically binds to tau, nor does the specification provide any examples of sequences lacking significant sequence identity with the disclosed CDRs (e.g., those present in SEQ ID NOs: 127 and 149). Examples are not provided of antibody derivatives that specifically binds to tau and have all the possible combinations recited in claim 8 or deviate significantly from the six CDRs of working sequences such as SEQ ID NOs: 127 and 149.
Amount of guidance or direction provided/Quantity of experimentation required: The specification only provides guidance regarding the effects of an antibody with specific CDRs and does not include any direction on how to prepare antibody or antigen-binding antibody fragments that specifically binds to tau that may be of the large variety of combinations of substitutions that still function as claimed. In the absence of working examples, undue experimentation would be necessary to determine the structure and scope of antibody or antigen-binding antibody fragment that specifically binds to tau (if any) that fall within the bounds of the claim, but which lack significant sequence identity with the specific CDR sequences disclosed, and/or that lack 100% identity to all six CDRs of several specific antibodies listed in the specification.
In summary, the claims allow for significant variations in the CDRs on the antibody or antigen-binding antibody fragment that specifically binds to tau and thus contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
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.
Previous rejection, withdrawn: claims 8, 18, 20 – 21, 26, 43, 98 – 105, 107 – 109, and 111 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.
In view of the claim amendments of the reply of 12/08/2026, this rejection is withdrawn.
Conclusion
Claims 8, 18, 20 – 21, 26, 43, 98 – 105, 107 – 109, and 111 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Estella Gustilo whose telephone number is (703)756-1706. The examiner can normally be reached Monday - Friday 9:30 AM - 5:30 PM.
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/ESTELLA M. GUSTILO/Examiner, Art Unit 1646
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647