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. In the response filed 5/6/26, Applicants elected Group I, drawn to the identified species, and traversed on the grounds that claim 49, which incorporates claim 51, is not taught by the prior art cited by the Examiner. This argument has been considered and is deemed persuasive insofar as the cited reference is concerned. However, in view of the rejection below, the restriction remains. Furthermore, any methods commensurate in scope with an allowed product will be considered for rejoinder. However, upon further review, all species have been examined. This restriction is deemed proper and is, therefore, made FINAL.
B. Claims 49, 50, 52-62 and 66-71 are pending. Claims 61 and 62 are withdrawn as being drawn to a non-elected invention. Claims 49, 50, 52-60 and 66-71 are the subject of this Office Action.
2. Specification
The specification is objected to since the Brief Description of the Figures (e.g. Figures) should be amended to initially reflect the panels. In other words, “Fig. 1A shows” should be amended to, for example, “Fig. 1A-1B show” or “Figures 1A-B. Figure A shows”. The use of “A” and “B” later in the description may be retained.
3. Claim Objections
A. Claim 52 is objected to since it ends with “from autologous or allogenic”, which is unclear.
B. Claim 56 is objected to since there should not be a comma after the first recitation of “wherein”.
C. Claim 59 is objected to since the syntax could be improved – more specifically, the claim recites “protein comprises…molecule is”. The claim could be amended to, for example, “comprises: (i) an endogenous CD94 molecule which is knocked out”.
D. Claims 67 and 70 are objected to since “single domain” should be hyphenated.
4. 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 49-51, 53-60 and 69-71 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. Other than the immune cells of claim 52, neither the specification, nor the claims provide adequate written description of other genetically engineered cells (see “genetically engineered cell” in claim 49).
Claim 49 requires a cell expressing an antibody, or other molecule which recognized CD94, as well as a TM and ISD. However, there is no guidance as to what cells, other than immune cells, are able to express either a molecule recognizing CD94, or a CAR able to recognize CD94. 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 cells other than those that form the genus in claim 52, 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, Claim 68 is 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 claim is broadly drawn to an antibody comprising only one of the required 6 CDRs. The specification only teaches that antibodies which specifically bind to CD94 comprise the sequence of the 6 CDRs recited in claim 69. The specification does not teach antibodies that comprise fewer.
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 fewer than all six full-length CDRs of, for example, claim 69, or any wild-type or parental antibody disclosed in the specification, 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 wild-type CDRs 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.
5. Claim Rejections - 35 USC § 112(b)
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.
A. Claims 49, 50 and 54 are rejected since the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
B. Claim 49 is confusing since it recites a “first protein” with no reference to a second protein. Claims 50-54, 56-60, 70 and 71 are rejected since they depend from claim 49.
C. Claim 53 is confusing. It recites that the endogenous B2M and TCR are knocked out; however, there is no requirement that the cell of claim 49 have these endogenous molecules.
D. Claim 56 is 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 claim is drawn to a cell. However, it further recites “wherein, the cell is administered”, which is a method claim. Claims 57-60 are rejected since they depend from claim 56.
6. Claim Rejections - 35 USC § 103
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 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 49, 70 and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Sivori et al. in view of Dean and Reddy. Claim 49 is drawn to a genetically engineered cell expressing a first protein recognizing CD94, wherein the gene encoding CD94 has low or no expression. It is noted that the transmembrane domain, intracellular signaling domain and SEQ ID NO:1 can be read as being optional. If claim 49 is interpreted as requiring a TM and ISD, then this rejection will be withdrawn.
Sivori teaches monoclonal antibodies to CD94 for the study of NK cells. Sivori is silent regarding expression of CD94. It is noted, however, that “low expression” in claim 49 is subjective.
Regardless, Dean and Reddy teach the use of CHO cells as a common method of expressing mammalian antibodies. Since CD94 is an innate immune receptor predominantly expressed on Natural Killer (NK) cells and certain T cell, CHO cells do not naturally express CD94. Therefore, given the importance of studying CD94 using antibodies, it would have been obvious at the time of the instant invention to have produced these antibodies using the method of Dean and Reddy given that CHO cells are well-known to be used for commercial production of protein, which would provide for larger amounts than the hybridoma of Sivori and would be more cost effective.
Regarding claim 71, though the gene is not knocked out, the cell would be the same regardless since, again, CHO cells do not express endogenous CD94.
7. Art of Interest Not Relied Upon
Regarding claim 50, Zhang teaches the development of a platform which enables high-titer CHO expression of T cell-related proteins, including soluble TCRs, TCR fusion proteins, and single chain trimers (second paragraph). However, though all of the domains recited in claim 50 were commonly used in CARs at the time of the instant invention, this reference cannot be used as prior art in combination with Dean and Reddy due to the fact that it was published no earlier than 2024. Furthermore, it is noted that parts (i) – (iv) are optional. Therefore, any prior art meeting the preamble would render the claim obvious,
8. Conclusion
A. Claims 49, 50, 52-60, 68, 70 and 71 are not allowable.
B. Claims 66 and 67 are free of the prior art and allowable.
C. Claims 68 and 69 are free of the prior art, but are not allowable since they depend from claim 49.
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
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