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 .
1. Formal Matters
A. Applicant’s election without traverse of Group I in the reply filed on 11/24/25, drawn to the elected species of SEQ ID NO:22 and 44, is acknowledged. Therefore, this restriction is deemed proper and is made FINAL.
B. Claims 1-14 and 18 are pending. As discussed below, claim 18 references two sets of claims to different features and is, therefore, an improper multiple dependent claim and is not further treated on the merits. Therefore, claims 1-14 are the subject of this Office Action. It is also noted that claim 18 depends from canceled claims15-17.
2. Claim Objections
A. In claim 14, the phrase “single chain” should be hyphenated.
B. Claim 18 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot reference two sets of claims to different features. See MPEP § 608.01(n). In the instant case, the claim refers to a method of claim 7 and a binding agent of claims 8-17. Accordingly, the claim has not been further treated on the merits. The example provided in MPEP 608.01(n)(I)(B)(3) states:
3. Reference to Two Sets of Claims to Different Features
Claim 9. A gadget as in claim 1 or 4 made by the process of claims 5, 6, 7, or 8, in which ---
3. Claim Rejections - 35 USC § 112(a) – written description
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.
A. Claims 1-7 and 12 are rejected under 35 U.S.C. 112, first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
These are genus claims. The claims are drawn to methods of treating ichthyosis by inhibiting IL-36 signaling. However, other than inhibiting IL-36, the specification and claims do not indicate what distinguishing attributes are shared by the members of the genus.
The term “IL-36 pathway” is broad and includes numerous signaling molecules (see Figures 1-3 of Yuan). Any inhibitor of any of these upstream or downstream molecules would be considered an inhibitor of IL-36 signaling. Thus, the scope of the claims includes numerous structural variants, and the genus is highly variant because a significant number of structural differences between/among genus members is permitted. Applicants have only identified inhibitors of IL-36, itself, wherein the inhibitors are antibodies (see also paragraph [0042] of the specification). In addition, Todorovic describes the small-molecule antagonist A-552. Therefore, the specification and claims only provide minimal guidance as to what changes should be made. Structural features that could distinguish compounds in the genus from others in the nucleic acid, protein, or small molecule class are missing from the disclosure. No common structural attributes identify the members of the genus.
The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed. Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, antibodies and A-552, alone, are insufficient to describe the genus. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus. Thus, Applicant was not in possession of the claimed genus at the time the invention was made.
B. Claims 8-12 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 claims are broadly drawn to antibodies which have substitutions (“Xaa”) in one or more CDR of the heavy and light chain in addition to known SEQ ID NOs:2-14, 16-24, 26-35, 51-54 for the heavy chain and SEQ ID NOs:37-39, 41-44, 46-50 and 55 of the light chain). However, the specification only teaches that antibodies which specifically bind to IL36 comprise SEQ ID NO:22 and 44 (Example 2). Therefore, antibodies other than SEQ ID NO:22 and 44, which include defined CDRs as well as Xaa’s, have CDRs that differ from SEQ ID NO:22 and 44 in one or more residues.
The nature of the invention is engineered antibodies where the relative level of skill of those in the art is deemed to be high. The state of the prior art is such that it is well-established in the art that the formation of an intact antigen-binding site of antibodies routinely requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, William E.), under the heading “Fv Structure and Diversity in Three Dimensions”). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30).
Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. Colman P. M. et al teaches that even a very conservative substitution may abolish binding or may have very little effect on the binding affinity (see pg. 35, top of left column and pg. 33, right column). Additionally, Bendig M. M. et al. reviews that the general strategy for “humanizing” antibodies involves the substitution of all six CDRs from a rodent antibody that binds an antigen of interest, and that all six CDRs are involved in antigen binding (see entire document, but especially Figures 1-3).
Similarly, the skilled artisan recognized a “chimeric” antibody to be an antibody in which both the heavy chain variable region (which comprises the three heavy chain CDRs) and the light chain variable region (which comprises the three light chain CDRs) of a rodent antibody are recombined with constant region sequences from a human antibody of a desired isotype (see entire document, but especially Figures 1-3). While there are some publications which acknowledge that CDR3 is important, the conformations of other CDRs as well as framework residues influence binding. MacCallum et al. analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right col.) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al., which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.).
In fact, even regarding CDR3, Scheffer et al. states “[t]herefore, many studies attempt to predict AIR-antigen binding exclusively based on the heavy/beta chain CDR3 sequences. Yet, the underlying rules determining whether an AIR can bind an antigen of interest remain unknown.” Furthermore, even within CDR3, Scheffer concludes “we have shown that there indeed exist motifs composed of a few amino acids in fixed positions of the antibody CDRH3, whose presence is nearly sufficient to predict antigen binding in a mutagenesis dataset where other variable regions were kept the same”. Applicants do not appear to show such a motif, nor would bind be predictable in the presence of changes to other CDRs.
Additionally, Valdes-Trescano (Section 2.3) states “[a]t the sequence region level, we observed a considerable variation in the accuracy of CDR modeling, especially for CDR3”.
Further, Chen et al. teach that the substitution of a single amino acid can totally ablate antigen and that the same substitution in closely related antibodies can have opposite effects binding (e.g., see entire document, including Figure I). For example, the authors compared the effects of identical substitutions in related antibodies DI6 and TI5, and as shown in Figure 3, some substitutions increased antigen binding in one antibody while ablating it in the other. As such, it is unpredictable which combination of random substitution has the recited function.
Finally, Ye teaches that “[t]he final data set contained 1157 antibodies and 57 antigens that were combined in 5041 antibody-antigen pairs. The best performance for the prediction of interactions was obtained by using the nearest neighbor method with the BLOSUM62 matrix, which resulted in around 82% accuracy on the full data set. These results provide a useful frame of reference, as well as protocols and considerations, for machine learning and data set creation in the prediction of antibody-antigen binding.
However, in this approach, “[s]everal machine learning approaches were compared to predict antibody-antigen interaction from protein sequences”. Therefore, even with a study using 1157 antibodies and 57 antigens, the best prediction was 82%. Again, it is noted that several machine learning approaches were used, showing that prediction can still be difficult and dependent on the prediction method used.
Thus, the state of the art recognized that it would be highly unpredictable that a specific binding member comprising an antibody comprising one or more substitutions to one or more of the six CDRs of a parental antibody (SEQ ID NO:22 and 44) with a desired specificity would retain the antigen-binding function of the parental antibody. One of ordinary skill in the art could not predictably extrapolate the teachings in the specification, limited to antibodies that comprise all 6 CDRs of SEQ ID NO:22 and 44 to antibodies that comprise alterations in one or more CDRs from the parental antibody.
In summary, in view of the lack of the predictability of the art to which the invention pertains as evidenced by the above references, the lack of guidance and direction provided by applicant, and the absence of working examples, the Examiner concludes that undue experimentation would be required to practice the invention as claimed.
4. 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 1-7, 13 and 14 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Fine et al. (US2022/0073628).
The claims are drawn to treating ichthyosis, including Netherton syndrome, by administering an inhibitor of IL-36 signaling. Claims 1 and 11 of Fine teach a method of inhibiting both conditions by administering an IL-36R antibody. Regarding instant claims 3 and 4, mammals, including humans, are taught in paragraph [0063] of Fine. Claims 5 and 6 are taught in paragraph [0052]. Claim 14 is met by paragraph [0080] of Fine.
Though currently not examined, in the interest of compact prosecution, claim 18 may be included in this rejection if it is limited to claim 7 since pharmaceutical compositions are taught in paragraph [0117].
5. Claim Rejections - 35 USC § 103
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 8-12 are rejected under 35 U.S.C. 103 as being unpatentable over Fine et al. (US2022/0073628) in view of Bowers et al. (U.S. Patent No. 10,526,410).
The teachings of Fine are seen above under 35 USC 102. Fine does not teach the individual antibody SEQ ID NOs. However, Bowers does.
SEQ ID NO:22
Patent No. 10526410
GENERAL INFORMATION
APPLICANT: AnaptysBio, Inc.
TITLE OF INVENTION: ANTIBODIES DIRECTED AGAINST INTERLEUKIN 36 RECEPTOR (IL-36R)
FILE REFERENCE: 723558
CURRENT APPLICATION NUMBER: US/15/567,045
CURRENT FILING DATE: 2017-10-16
PRIOR APPLICATION NUMBER: US 62/147,824
PRIOR FILING DATE: 2015-04-15
NUMBER OF SEQ ID NOS: 58
SEQ ID NO 22
LENGTH: 120
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Synthetic Sequence
Query Match 100.0%; Score 635; Length 120;
Best Local Similarity 100.0%;
Matches 120; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWMNWVRQAPRQGLEWMGMFHPTGDVTRL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWMNWVRQAPRQGLEWMGMFHPTGDVTRL 60
Qy 61 NQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARTTSMIIGGFAYWGQGTLVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARTTSMIIGGFAYWGQGTLVTVSS 120
SEQ ID NO:44
SEQ ID NO 44
LENGTH: 112
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Synthetic Sequence
Query Match 100.0%; Score 586; Length 112;
Best Local Similarity 100.0%;
Matches 112; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIVMTQTPLSLSVTPGQPASISCRSSKSLLHRNAITYFYWYLHKPGQPPQLLIYQMSNLA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIVMTQTPLSLSVTPGQPASISCRSSKSLLHRNAITYFYWYLHKPGQPPQLLIYQMSNLA 60
Qy 61 SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCAQNLELPLTFGGGTKVEIK 112
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCAQNLELPLTFGGGTKVEIK 112
Though currently not examined, in the interest of compact prosecution, claim 18 may be included in this rejection since pharmaceutical compositions are taught in paragraph [0117] of Fine.
6. Conclusion
No claim is allowable.
Advisory information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT S LANDSMAN whose telephone number is 571-272-0888. The examiner can normally be reached M-F 8 AM – 6 PM (eastern).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
/ROBERT S LANDSMAN/Primary Examiner, Art Unit 1647