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 .
Election/Restrictions
Applicant’s election without traverse of the anti-CDCP1 antibody having HCDR1-3 of SEQ ID Nos. 73, 147, and 75 and with the LCDRs1-3 of SEQ ID Nos. 149, 78, and 79 as well as MMAE in claims 13-14, in the reply filed on 10/17/2025 is acknowledged.
Claims 3-8, 10, and 17-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/17/2025.
Claim Status
Claims 1-2, 9, and 11-16 are under examination.
Claims 3-8, 10, and 17-20 are withdrawn.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
No translation is provided of the priority document JP2019-238928 and so no priority of its filing date is given to any claim.
The disclosure of the prior-filed application, Application No. JP2019-238928, even if it were identical to the instant disclosure, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application for the same reasons below that the instant disclosure fails.
Thus, all claims under examination must only receive the U.S. effective filing date of 12/24/2020.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The information disclosure statements (IDS) submitted on 06/24/2022, 05/24/2023, and 07/03/2023 are being considered by the examiner.
Drawings
The drawings are objected to because Figures 1, 4-5, 7-8, 13, 16, 17B and 19 are not legible. Also, Figure 8 contains non-English text. In addition, Figures 5 and 6 are labeled in the opposite direction as their graphs or images. The labels Fig. 5 and Fig. 6 should be in landscape format if the images/graphs are landscape format and portrait layout if said images/graphs are portrait layout.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
The sequence is at 0076 (6xHis).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Figures 6A-6B require a sequence identifier for each sequence. Of note, this includes for each mutation/variant taught as the full length of each chain is clearly shown by the figures even if only a dipeptide labels each variant.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities: Table 1 at 0084 is not legible. Also, Table 7 at 0102 is not legible.
Appropriate correction is required.
The use of the terms SEPHAROSE (0020), FLAG (0076), HISTRAP (0076), HITRAP (0076), COMPLETE (0077), NUCLEOFECTOR (0078), TITERMAX (0082), EZ-LINK (Pg. 61), ALPHALISA (Pg. 63), SEPHADEX (Pg. 70) and MATRIGEL (Pg. 77), each of which is a trade name or a mark used in commerce, has been noted in this application. Each term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure is objected to because it is too long. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claim 9 is objected to for lacking the antigen target of the antibody. Such will better represent the invention.
Claim 15 is objected to because of the following informalities: the term “a” is required at the end of line 1.
Appropriate correction is required.
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.
Claims 1-2, 9, and 11-16 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.
The term “low” in claims 1-2 and 11 is a relative term which renders the claims and their dependents indefinite. The term “low” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification provides no definition of low. Since the term is relative and subjective every practitioner could have a different standard of what low. Thus, the claims are currently subject to a plethora of interpretations and this renders the claim indefinite.
Claim 2 is further indefinite for reciting a generic comparative antibody. Since said antibody could be used as an example of low affinity, high affinity, or some cut-off affinity to establish what is lower binding, it has multiple interpretations. It is also not clear if the concentration of said control antibody must be the same as the test antibody of claim 1. This also gives the claims multiple interpretations. Lastly, it is not clear if the antigen binding fragment is of the antibody of claim 1 or the comparative antibody. Again, the presence of multiple interpretations renders the claim indefinite.
Claim 9 is rendered indefinite since the term antibody is defined to include both polyclonal and monoclonal antibodies (0020). This gives the claim and its dependents multiple interpretations. First, all CDRs could be present on one molecule. Second, the CDRs in the polyclonal antibody could be divided amongst multiple antibody molecules since polyclonal antibodies have multiple and different antibody species. The presence of multiple structural interpretations renders the claims indefinite. The same rejection is made for claim 11 owed to dependency as without clarity of the structure of claim 9, the competing antibody is indefinite.
Claim 11 also recites antigen binding fragment thereof but it is not clear whether this is such a fragment of the competing antibody or a fragment of the antibody of claim 9.
See Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) ("[R]ather than requiring that the claims are insolubly ambiguous, we hold that if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite.").
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 16 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 16 recites a pharmaceutical composition comprising the antibody of claim 1. However, the antibody of claim 1 is already a pharmaceutical composition of matter and the specification provides no definition of composition to provide a further limitation. Thus, claim 16 does not further limit the claim on which it depends and is rejected here.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-2, 9, and 11-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for anti-CDCP1 antibodies and antigen binding fragments thereof each comprising all six complete, parental CDRs of a functional antibody, does not reasonably provide enablement for any antibody or antibody-like molecule with fewer than all six complete, parental CDRs. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The breadth of the claims is found in claim 1 drawn to an antibody that binds to human CDCP1 having a low binding property to human CD34+ cells or an antigen binding fragment thereof. It is noted that said fragment can be a single variable region (nanoantibody) or CDR (0026).
The nature of the invention is an anti-cancer antibody against CDCP1.
The level of skill of one skilled in this art is high.
The specification teaches the breadth of the claimed binding fragments as discussed above, as well as exemplary species of anti-CDCP1 monoclonal antibodies in Table 2 on page 53. All CDRs are murine or modified murine CDRs (0085). There are approximately 34 antibodies listed derived from six functional parental clones (0087 and 0085). All 34 antibodies bind antigen but all use six CDRs to do so (0088).
The fragments claimed would not be expected to be functional to their full breadth as discussed below.
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 generally 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, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, 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).
Additionally, Bendig M. M. (Methods: A Companion to Methods in Enzymology, 1995; 8:83-93) 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). It is noted that Bendig used Kabat CDRs in their humanization process (Pg. 86, Column 2, Paragraph, second). 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).
Thus, the state of the art recognized that it would be highly unpredictable that a specific antibody comprising less than all six parental CDRs would have antigen binding function. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of a murine or humanized antibody includes six CDRs (three from the heavy chain variable region and three from the light chain variable region) in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function. One of skill in the art would neither expect nor predict the appropriate functioning of the antibody fragments of instant claims as broadly as claimed.
Furthermore, the polyclonal embodiments of claims 9 and 11 are not enabled as they allow for antibody molecules to be defined by fewer than all complete parental CDRs. See the indefiniteness rejection above, all incorporated here, for a discussion of this structural interpretation. Bendig showed substitution of all six CDRs was required for antigen binding function as discussed above and so defining an antibody by one CDR or substitution of only one, while allowing others to be what would be considered mutated versions of parental CDRs as they are undefined by the claim in this embodiment, is not enabled as the resultants would not predictably bind antigen.
In the case of antibodies, it is especially important to disclose which residues are permissive to mutation. 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. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982). 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 (Abstract). Thus, all claims with any antibody molecule embodiment defined by fewer than all six complete parental CDRs lacks enablement and is rejected here.
Not knowing, absent further experimentation, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect antibody structure and function, leads to one having no predictability or expectation of success for the function of any given antibody modification. Such random experimentation to identify at a later time what structure or fragment or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation.
Instant claims 9 and 11 also read on or use monoclonal antibodies that comprise the CDRs of claim 9. A complete set of CDRs for patent purposes should include CDRs that are known to confer antigen binding to a non-parental framework. As mentioned above in the work of Bendig, Kabat CDRs can be moved to a different framework, such as during humanization, and confer antigen binding. The examiner is unaware of any showing in the art that other types of CDRs have the same capacity.
The art confirms that Chothia CDRs are not complete CDRs. Dubel (Handbook of Therapeutic Antibodies, 2007, Pg. 100-101) teaches that Chothia CDRH1 is a structural loop that does not include the complete CDR (Pg. 100, Paragraph, final). They conclude that the analysis of classes by Chothia is based on structural loops rather than the full CDRs (Pg. 100-101, Paragraph, spanning). Thus, Chothia CDR sets cannot be considered complete. They also confirm that Chothia definitions of CDRs change over time and so are not consistently defined (Pg. 101, Paragraph, first). It is further noted that IMGT introduced a range of residues for the same loops and they confusingly term these CDRs (Pg. 101, Paragraph, fourth). Thus, it is clear that the art does not consistently recognize IMGT CDRs as complete.
Johnson and Wu (Methods in Molecular Biology, Antibody Engineering: Methods and Protocols, Vol. 248, Pg. 11-25, 2004) teach that complete CDRs of antibodies CDRH1-3 and CDRL1-3 are at least 5, 16, 8, 11, 7, and 9 amino acid residues in length respectively (Pg. 12, Paragraph, second full). In instant claim 9, CDRH3 has 7 residues and CDRL1 has 10 residues. These are significantly smaller than the CDR lengths of Kabat CDRs and so would not be expected to confer antigen binding to an antibody framework barring evidence to the contrary. They amount to no more than mutated Kabat CDRs. Mutated CDRs would not predictably bind antigen as discussed above. Therefore, even a monoclonal antibody comprising the CDRs of claim 9 is not enabled. Barring experimental evidence, such mutated and truncated CDRs would be insufficient to confer antigen binding function.
Moreover, claims not containing elements critical or essential to the practice of the invention, such as antibodies or antibody fragments not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate antibody heavy or light chain framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional antibodies or fragments thereof comprising fewer than all six complete, parental CDRs or comprising mutated versions thereof, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
It is recommended that Applicant add the term monoclonal before each use of antibody in the claims to at least avoid the issues caused by the polyclonal embodiment above. Evidence should also be presented to show functionality of the claimed monoclonal antibodies commensurate in scope with the claims.
Claims 1-2, 9, and 11-16 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 instant claims above are drawn to a genus of antibodies, including monoclonal antibodies, defined by the epitope they bind and additional functional language as in claim 1 or 11 (competition) or at least partial CDR set structure as in the polyclonal embodiment of claim 9. No claim is defined at least in part by a full set of complete, parental CDRs. Of note, the low binding property in all claim that recite this phrase has no lower limit and so exceeds any limit disclosed for any antibody in the specification. When one goes to the instant specification to identify a representative number of species to define the claimed genera with respect to antibodies with six CDRs that bind the recited antigen and/or containing any one CDR of claim 9, they find exemplary species of anti-CDCP1 monoclonal antibodies in Table 2 on page 53. There are approximately 34 antibodies listed derived from six functional parental clones (0087 and 0085). All 34 antibodies bind antigen but all use six CDRs to do so (0088). Thus, no fragment is taught to be functional with fewer than all six CDRs. All 34 clones and the CDR sets of each could meet the limitation of claim 1 but only 3 have at least one CDR of claim 9 and only said 3 would be expected to compete with the antibody of claim 9 as their CDR sets are related, while the other clones lack such similarities (0085 and Table 2 and Figures 6A-B). Even if the prior art is aware of additional antibodies, the totality of known antibodies would not be representative of each entire genus for the reasons discussed below.
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been evaluated in view of that guidance.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
Furthermore, to satisfy the written description requirement for the genus antibody with specific epitope, Applicant must adequately describe representative antibodies to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F.3d at 1568 (“[N]aming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) (“Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the antibodies claimed can have any CDR set, one must describe a sufficient variety of species to reflect the variation within the genus. One of skill in this art cannot envision the structure of any other antibodies that bind CDCP1 or do so by competing with the clone of claim 9 or with any one CDR of claim 9 in its binding site other than the species provided by Applicant stated above. All variants here originate from six parental clones (0085) and so at most, six families of antibodies are taught to represent the genera claimed in claim 1, for example, while only 3 highly related clones (one family) are taught to represent the genera of claims 9 and 11. Therefore, the claims encompassing the same clearly fail the written description requirement.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
“Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010). Since the CDR set of each antibody is responsible for antigen binding function of an antibody, and said set varies structurally from antibody to antibody, there is no correlation between structure and function between the members of an antibody genus. Thus, functional language should not be used to define an antibody genus. Rather, structure should be used.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus. Three species is certainly not adequate. Having 34 species which can be sorted into six groups of highly related species as in the case of the Joe-9 variants is equally inadequate.
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
Since only a few species of antibodies are taught within the claimed genera above, the instant claims above clearly fail the written description requirement. A representative number of species has not been taught to describe these genera. Given the well-known high level of polymorphism of immunoglobulins / 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. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera.
Owed to the variation among antibodies with respect to their CDRs, the structure of antibodies that correlates with their function, it is very difficult to provide adequate representation of a functionally defined antibody genus. There is unlikely to be any CDR structure shared by the entire genus, for example. Also, the disclosure of one set of antibody CDRs does not guide one of skill to the next set of CDRs. This is because it is well-known in this art that mutation of CDR residues leads to loss of antigen binding. 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. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982). 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 (Abstract). Thus, while Applicant has described a few highly related species within each of the genera recited, and the art may provide more, each genus is very large and would encompass antibody structures (CDR sets) that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the antibody structures encompassed by the claimed genera only defined by function. Any future antibody structure may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the recited genera of antibodies. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here.
As discussed above, an applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613. Therefore, it is recommended that the instant claims be amended to recite all parental CDRs of the species disclosed since it is these structures together that are required to bind the recited antigen and that the term monoclonal be used in front of each recitation of antibody.
Claim 11 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. This is a new matter rejection.
Claim 11 has been amended to recite an antibody that competes with binding of the antibody of claim 9. However, when one goes to the original specification, they do not find this claimed subgenus. Rather, they find only a broader genus of a competing antibody with the “first embodiment” (Pg. 29), no part of which contains the exact CDRs of claim 9. Even if a different subgenus were contemplated of a competitor with the parental clone of the antibody of claim 9, this is still not equivalent to the claimed subgenus as the two subgenera will have different scopes owed to different affinities of the parental clone and its variant. Therefore, the subgenus recited in claim 9 was not originally taught and is new matter.
While the specification may be sufficient to render claim 9 obvious, this is not the same as original contemplation or teach and shows instead such was not taught as it would have to be made obvious from the original disclosure.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1-2, 12 and 16 are rejected under 35 U.S.C. 102a1 as being anticipated by Auer (US2011/0052582, published 03/03/2011, previously cited).
Auer teaches an antibody against human CDCP1 and a humanized version thereof (0011-0025). These antibodies meet all the structural and functional limitations of instant claim 1 for the following reasons. The structure is met owed to specificity and antibody nature. The function is met because “low” binding property is relative, subjective and indefinite. Thus, to whatever extent Auer’s antibody binds human CD34-positive cells it is “low” affinity. Furthermore, the function of claim 1 is subject to assay type and conditions and the result is dependent on the cells used. For example, one can put human CD34 in CHO cells and expect low binding of the antibody of Auer as its target is not expressed. In addition, one can take a human cell line with CD34 and knockout/knockdown CDCP1 and expect a low binding thereof by the antibody of Auer. Thus, the prior art clearly contains antibodies meeting all the requirements of instant claim 1, anticipating the same. The same can be said for claim 2 as broadly as currently claimed and in view of the examples above.
Claim 12 is met as discussed above.
With respect to claim 16, Auer teaches pharmaceutical compositions comprising their antibodies (Abstract).
Thus, the claims are clearly anticipated.
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.
Claim(s) 1-2, 11, and 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Cantley (US2022/0119545, with priority to 11/09/2018) in view of Casar (Oncogene, Vol. 33, No. 2, Pg. 255-268, 2014).
Cantley teaches materials and methods for CDCP1-targeted therapy (Abstract). CDCP1 is a target for therapeutic intervention in patients with a variety of cancers (0006). They teach a method of treating cancer comprising administering an agent which binds to CDCP1 (0007). The anti-CDCP1 agent can be an antibody or antigen-binding fragment thereof (0015) such as a polyclonal antibody or fragments like Fab and Fv (0016 and 0228). Importantly, in some cells the extracellular domain of CDCP1 is cleaved to produce a 75kDa transmembrane protein (0226) and the CDCP1 can be human (0227).
Thus, Cantley has called out various types of antibodies against CDCP1 and said target can be human. Thus, all these antibody types would have been obvious to a PHOSITA before the filing of the instant application for use in predictably binding human CDCP1. Such an obvious embodiment would be a polyclonal full-length antibody or polyclonal Fab antibody. Both would predictably bind the target of Cantley and are encompassed by their teachings.
Furthermore, the PTAB has taken the position that once an antigen has been isolated, the manufacture of monoclonal antibodies against it is prima facie obvious. See Ex parte Ehrlich, 3 USPQ 2d 1011 (PTO BPAI, 1987) and Ex parte Sugimoto, 14 USPQ 2d 1312 (PTO BPAI, 1990). The examiner holds this to be true for polyclonal antibodies as well since most monoclonal antibodies are produced by immunization and thus the production of a polyclonal antibody first. See 0244 of Cantley with reference to the hybridoma method.
As a logical extension, the obvious polyclonals above would have been equally obvious to produce against the 75kDa variant of human CDCP1. Since said protein is known by structure and thus isolated, an antibody against it is obvious.
Indeed, the prior art was well aware of this cleaved variant and prognoses using the same.
Casar teaches specific cleavage of CDCP1 by serine proteases induces outside-in signal transduction that facilitates early stages of metastasis leading to tumor cell intravasation (Abstract). They further state that CDCP1 cleavage may represent a therapeutic target for CDCP1+ cancers (Abstract). They teach this for human CDCP1 (Pg. 2, Paragraph third) as they use human cells in their study. The cleavage generates a 70 kDa fragment of CDCP1 (Pg. 4, Paragraph, first) and so is the same or similar event taught by Cantley above.
Taken all together, it would have been obvious to a PHOSITA before the filing of the instant application that the obvious full-length antibodies or fragments thereof above against the cleaved CDCP1 of Cantley or Casar, all polyclonal, could be used to prognose increased risk of cancer metastasis owed to the nexus between cleavage/removal of the extracellular domain of the human CDCP1 protein (since Casar teaches the cleavage product is membrane-retained (Pg. 2, Paragraph, second) and cancer cell intravasation discussed above. Thus, these tools would have been obvious to a PHOSITA for the advantage of prognosing CDCP1-expressing cancers for motility risk. They would predictably function in this method as polyclonal antibodies or fragments thereof are routinely used in protein detection methods in this art.
Of note, the polyclonal antibodies and fragments above will contain an antibody species for every epitope of the cleaved target human CDCP1. Thus, they will predictably compete with the antibody of instant claim 9 raised against the same.
The obvious antibodies meet all structural and functional limitations of all claims above therefore as any binding property they have against CD34+ cells will be “low” in at least some examples as discussed supra in the 102, said examples of CHO cells and knockdown/out being incorporated here.
With respect to claim 13-14, the antigen binding fragments above made obvious meet the claim limitations of the fragments which need not bind another substance.
With respect to claim 16, it is standard practice in this art to use an aqueous carrier with antibodies for prognostic assays like the obvious one above and so a pharmaceutical composition comprising the obvious anti-cleaved human CDCP1 polyclonal antibody or Fab is obvious here.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL D ALLEN whose telephone number is (571)270-3497. The examiner can normally be reached Mon-Fri 10-6.
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, Samira Jean-Louis can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Michael Allen/Primary Examiner, Art Unit 1642