DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
Applicant's amendment and remarks, filed 1/5/26, are acknowledged.
Claim 13 has been amended.
Claims 1-2, 4-10, 13, 15-20, 27, 29, 33-34, 36-39, 47-49 are pending.
Claims 1-2, 4-10, 27, 29, and 36-38 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claims 13, 15-20, 33-34, 39 and 47-49 are being acted upon.
The 112b rejections are withdrawn in view of Applicant’s claim amendments.
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 13, 15-20, 33-34, 39 and 47-49 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the enablement requirement. The claim(s) contains 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 specification disclosure is insufficient to enable one skilled in the art to practice the invention as claimed without an undue amount of experimentation. Undue experimentation must be considered in light of factors including: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill in the art, the level of predictability of the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention, see In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) states, “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” “The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling” (MPEP 2164.03). The MPEP further states that physiological activity can be considered inherently unpredictable. With these teachings in mind, an enabling disclosure, commensurate in scope with the breadth of the claimed invention, is required.
The instant claims are directed to a method for producing a therapeutic anti-human ILT7 modified monoclonal antibody, wherein the monoclonal antibody comprises specific VH and VL SEQ ID Nos of claim 13, said method comprising administering to a non-human animal an exogenous cell expressing an extracellular domain of human ILT7 molecule and selecting an antibody producing cell that produces said antibody having the specific VH/VL SEQ ID Nos. from the non-human animal. The state of the art is such that antibody variable regions are composed of a heavy and light chain, each involved in providing for binding specificity. Variability in the antigen binding site is achieved by V(D)J recombination via heavy and light chain pairing, with the most diverse regions being the 6 CDR regions in the heavy and light chain. Thee antibody repertoire is extremely large, on the order of at least 1011, with a large degree of diversity in both heavy and light chains. These can also be further varied by a process of somatic hyper mutation. Furthermore, the diversity of the immunoglobulin repertoire is mediated in part by different combination so heavy and light chain V regions that pair to form a unique antibody binding site. See, for example, Rabia, 2018, which teaches that the maximal chemical diversity of antibody CDRs is unimaginably large and is extremely challenging to define the sequence determinant of antibody specificity (see page 4). Furthermore, the antibody repertoire has different amino acid sequences depending on the species, for example, mice will have different VH, VL, and CDR sequences as compared to other non-human animals. Additionally, immunization to induce antibodies results in unique antibody clonotypes with unique VH/VL sequences. For example, immunization of mice can result in a clonal diversity and distribution of CDR3 sequences comprising millions of different antibody producing cells, and the antibody repertoire of even inbred mice immunized with a medium complexity antigen contains few shared clones (see Greiff, page 8, in particular). Thus, based on the state of the art, immunization of, for example, even an inbred mouse strain with the claimed ILT7 expressing cell would result in millions of different antibody CDR sequences, and making an antibody with defined VH/VL sequences by merely administering an antigen and selecting antibody producing cells that have said VH/VL would be highly unpredictable. Furthermore, the claims encompass producing said antibodies with defined VH/VL sequence using any non-human animal, which would also be highly unpredictable due to the diversity of antibody sequences in different types of animals.
Thus, based on the breadth of the claims and the unpredictability of the art, the instant specification must provide an sufficient and enabling disclosure commensurate in scope with the instant claims.
The specification discloses administration of ILT7 expressing cells to Balb/c mice and selecting and screening antibody producing cells by creating hybridomas and testing for binding function to ILT7. Three ILT7 antibodies were sequenced, each having completely different CDR sequences and different VH?VL, as defined in claim 13. To make the monoclonal antibodies having said defined VH/VL sequences, the specification discloses that cells are transformed with nucleic acid sequences encoding the VH/VL, the cells are cultured, and the monoclonal antibody is recovered from the cells. Alternatively, the specification discloses deposited hybridoma cells lines that are a renewable source of the claimed antibodies. Thus, consistent with the state of the art, the specification discloses that immunization with an ILT7 expressing cell induces unique antibody producing cells, and selecting said cells provides for unique clonotypes having unique VH/VL sequences. Simply repeating the process of immunization that was used to provide the unique VH/VL sequences of the present claims would result in millions of different antibody producing cells, each comprising unique VH/VL sequences. Obtaining the claimed VH/VL sequences from the millions of different possibilities would require undue experimentation due to the diversity of antibody clones induced after immunization. The specification discloses that producing monoclonal antibodies with defined VH/VL sequences can be performed by culturing the deposited hybridoma cells, or by transforming a host cell with a nucleic acid sequence encoding the antibodies, but no guidance is provided as to how a monoclonal antibody with defined VH/VL could be produced by immunizing any non-human animal and selecting an antibody producing cell having said VH/VL. Thus based on the breadth of the claims, the unpredictability of the art, and the lack of guidance provided by the instant specification, it would require undue experimentation to practice the claimed method.
Applicant’s arguments filed 1/5/26 have been fully considered, but they are not persuasive.
Applicant argues that sequence defined antibodies are enabled if the specification provides the sequence information and routine recombinant methods to produce the antibody.
The claims are not directed to a sequence defined antibody. Nor are the claims directed to a routine, art recognized, recombinant methods for producing sequence defined antibodies. Rather, the claims are directed to a method of producing sequence defined antibodies by a process of immunization and selection of antibody producing cells, wherein the method comprises a step of selecting a cell that produces a sequence defined antibody having a defined VH/VL amino acid sequence.
Applicant argues that the specification provides working instructions that enable the method of claim 13, since in Examples 1 and 2, it teaches isolating antibody producing cells, and the antibodies having the defined VH/VL are the exact antibodies disclosed in Example 6. Applicant argues that the “selecting” step of the claims is performed via concrete reproducible screening assays as provided in Examples 3-5.
Examples 3-5 are screening assays used to identify cells that produce ILT7 binding antibodies having particular functional features and do not involve selecting sequence defined antibodies. In other words, the specification discloses screening assays that can be used to identify a sequence generic antibody of particular ILT7 binding function. The sequence of the antibodies selected in Examples 3-5 is not known or predicted by the screening assays. None of the examples involve identifying or selecting antibodies having a known, defined VH/VL sequence, as recited in the present claims. The only methods of producing sequence defined antibodies disclosed by the specification are those involving routine recombinant methods, where a particular VH/VL nucleic acid sequence is introduced into a host cell. As noted above the antibody repertoire of VH/VL sequences is extremely large, on the order of 1011, and even inbred mice immunized with a medium complexity antigen contains few shared clones. In other words, repeating the immunization process used in the specification would not even necessarily result in antibody producing cells having the same VH/VL sequences recited in the claims. Even if it did, they would be present in the immunized mouse along with potentially millions of other different VH/VL sequences that are specific for the immunizing antigen. The only way to “select” the claimed VH/VL sequences would be to select an antibody producing cell that produces an antibody that binds ILT7 and to sequence the resulting antibody by a trial and error process involving sequence potentially millions of different possibilities with no expectation of success that any particular antibody producing cell would have the recited VH/VL. Furthermore, as noted above, the claims are not even limited to immunizing a mouse, but would encompass immunizing a rat, which would have completely different VH/VL sequences than those claimed. It would require undue experimentation to practice the method of producing therapeutic anti-ILT7 monoclonal antibody that have specifically recited VH/VL sequences.
The following are new grounds of rejection necessitated by Applicant’s amendment.
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.
Claim 13, 15-20, 33-34, 39 and 47-49 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.
Claim 13 is indefinite in the recitation that the monoclonal antibody comprises amino acid sequences according to “any of the” in the heavy chain variable region and the light chain variable region
i) SEQ ID NO: 39 and SEQ ID NO: 41
SEQ ID NO: 43 and SEQ ID NO: 45
SEQ ID NO: 47 and SEQ ID NO: 49.
There is no modification to “any of the” and it is not clear what is encompassed. For example, do the claims mean any of the CDRs from the recited sequences, any of the recited embodiments i-iii)? There is also no “and” or “or” separating elements i)-iii). Do the claims mean to that the monoclonal antibody has all of the recited SEQ ID Nos, for example? The scope of the claims is unclear and indefinite. For the purposes of examination, the claims are being interpreted as being directed to monoclonal antibodies comprising heavy chain variable region and light chain variable region sequences comprising:
i) SEQ ID NO: 39 and SEQ ID NO: 41;
ii) SEQ ID NO: 43 and SEQ ID NO: 45; or
iii) SEQ ID NO: 47 and SEQ ID NO: 49.
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 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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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644