DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s election of Group I (claims 1, 4-12, 17-18, 22, 24-25, 27, 30, 41 and 52) and species of via natural amino acid in the reply filed on 9/10/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
3. Claims 1, 4-12, 17-18, 22, 24-25, 27, 30-33, 35-36, 39, 41-43 and 52 are pending. Claims 2-3, 13-16, 19-21, 23, 26, 28-29, 34, 37-38, 40 and 44-51 are canceled. Claims 31-33, 35, 36, 39 and 42-43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/10/2025.
4. Claims 1, 4-12, 17-18, 22, 24-25, 27, 30, 41 and 52 are under examination.
Information Disclosure Statement
5. The information disclosure statement filed on 9/23/2022 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because the date for NPL Cite Nos: 2 and 3 is not provided. It has been placed in the application file, but the information referred to therein has not been considered as it pertains to these items.
37 C.F.R. 1.98 (b)(5) Each publication listed in an information disclosure statement must be identified by publisher, author (if any), title, relevant pages of the publication, date, and place of publication.
6. The information disclosure statement filed on 9/26/2024 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because the date for NPL Cite No: 2 is not provided. It has been placed in the application file, but the information referred to therein has not been considered as it pertains to this item.
It also fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. It has been placed in the application file, but the information referred to therein has not been considered as it pertains to NPL Cite No.2.
7. The information disclosure statement filed 8/18/2025 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. It has been placed in the application file, but the information referred to therein has not been considered as it pertains to NPL Cite Nos.3 and 4.
Nucleotide and/or Amino Acid Sequence Disclosures
8. 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:
9. 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). See Figure 1A and 1B. Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
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.
10. 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.
Specification
11. The use of the term “nanobody”, which is a trade name or a mark used in commerce, has been noted in this application ([00045], [00054], [000129]). The 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.
Claim Objections
12. Claims 7, 10-11 and 18 are objected to because of the following informalities:
In claim 7, the term “or” should be added after “SEQ ID NO:14” if applicant does not intend to claim an antibody comprising all the sequences.
Claim 10 is objected to for reciting “optionally” and “or optionally” because it is unclear whether the limitations following the phrase are part of the claimed invention.
Claim 11 is objected to for reciting “modification” and “enhances” without a reference.
Claim 18 is objected to as the meanings of the terms “ds diabody”, “dsFv”, “bsFv”, “ds(Fv)2”, “dsFv-DsFv’”, and “ds diabody” are not clear. To avoid any ambiguity, the full terminology for these terms should be included in the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
13. 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.
14. Claim 18 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.
Claim 18 contains the trademark/trade name Nanobody[Symbol font/0xE2]. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a specific antibody and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 112
15. 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.
16. Claims 1, 4-6, 8-12, 17-18, 22, 24-25, 27, 30, 41 and 52 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.
Claims 1, 4-6, 8-12, 17-18, 22, 24-25, 27, 30, 41 and 52 encompass a genus of antibodies characterized by comprising less than 6 CDRs of a parental antibody and having a function of specifically binding to FGFR2b and FGFR1b, and having no detectable binding affinity to FGFR2c. The specification does not adequately describe all the species encompasses by the genus.
“[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.
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).
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are 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, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For antibodies, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor, 97 USPQ2d at 1875 (“[T]he application only provides amino acid sequence information (a molecular description of the antibody) for a single mouse variable region, i.e., the variable region that the mouse A2 antibody and the chimeric antibody have in common. However, the mouse variable region sequence does not serve as a stepping stone to identifying a human variable region within the scope of the claims.”). A chimeric antibody shares the full heavy and light chain variable regions with the corresponding mouse antibody; that is, the structure shared between a mouse and chimeric antibody would generally be expected to conserve the antigen binding activity.
Lastly, even if a selection procedure is disclosed that 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, 94 USPQ2d at 1167; Centocor at 1876 (“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.”)
Claims 1, 4-6, 8-12, 17-18, 22, 24-25, 27, 30, 41 and 52 encompass a genus of antibodies characterized by comprising less than 6 CDRs of a parental antibody i.e. clone Ab 21.
The terms “single domain antibody”, “domain antibody”, “Nanobody” in claim 18 each only comprise 3 CDRs of a parental antibody.
The specification discloses a mouse antibody Ab 21, a chimeric antibody thereof, and two humanized antibodies thereof, i.e. Ab hu21-21 and Ab hu21-26 (Examples 2 and 3). Ab hu21-21 comprises all 6 CDRs of mouse antibody Ab 21. Ab hu21-26 comprises all 6 CDRs of Ab 21 with a single mutation G56R in HCDR2. The specification does not disclose any other antibodies comprising less than 6 CDRs of Ab 21 including single domain antibodies, and having the claimed function (binding to FGFR2b and FGFR1b, and having no detectable binding affinity to FGFR2c). Therefore, the written description is not commensurate in scope with the claimed invention.
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). 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 (Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, March 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. Murphy et al. (Journal of Immunological Methods, Vol. 463, Pg. 127-133, 2018), teach that altering amino acid D92 in the complementarity determining region light chain region 3 (CDRL3) of single chain fragment variable (scFv) 2G1 obliterates its capacity to bind to microcystin-leucine-arginine (MC-LR)(Page 130, Section 3.2, paragraph 2) and changing phenylalanine at position 91 to tyrosine caused an increased in binding to MC-LR, compared to the parent clone (Page 131, Column 1, Paragraph 2). The alterations in binding that were observed in these two variants demonstrate the highly influential role of CDRL3 in binding MC-LR. Thus, the state of the art recognized that it would be highly unpredictable that a specific humanized antibody comprising less than all six CDRs of a parental antibody with a desired specificity would retain the antigen-binding function of the parental antibody. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of the parental donor antibody includes six CDRs (i.e. VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3) from parental donor antibody in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function of the parental donor antibody. One of ordinary skill in the art could not predictably extrapolate the teachings in the specification, limited to antibodies that comprise all six CDRs of a parental donor antibody that binds antigen to antibodies that comprise fewer than all six CDRs from the parental donor antibody, wherein the antibodies retain the antigen specificity of the parental donor antibody. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). This is because it is not obvious from the disclosure of one particular species, what other species will work. See MPEP 2164.03.
Ab hu 21-26 is not a representative number of species for the genus because the genus encompasses antibodies comprising any mutations in any CDRs of the parental antibody and having the claimed function. The specification also fails to disclose a correlation between the recited partial structure (less than 6 CDRs) and binding function. Because the minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of the parental donor antibody includes six CDRs (i.e. VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3) from parental donor antibody in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function of the parental donor 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, the members of the genus having the recited partial structure and function.
Accordingly, the skilled artisan would not recognize that applicants were in possession of the invention as broadly claimed at the time the application was filed.
Claim Rejections - 35 USC § 112
17. Claims 1, 4-6, 8-12, 17-18, 22, 24-25, 27, 30, 41 and 52 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for an antibody comprising all six CDRs (i.e. VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3) of a parental antibody and specifically binding to FGFR2b and FGFR1b and having no detectable binding affinity to FGFR2c, does not reasonably provide enablement for antibodies comprising less than 6 CDRs (i.e. VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3) of a parental antibody and having the claimed function. 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 and/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CAFC 1988).
Wands states on page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.''
The nature of the invention is engineered antibodies where the relative level of skill of those in the art is deemed to be high.
Claims 1, 4-6, 8-12, 17-18, 22, 24-25, 27, 30, 41 and 52 encompass a genus of antibodies characterized by comprising less than 6 CDRs of a parental antibody and having a function of binding to FGFR2b and FGFR1b, and having no detectable binding affinity to FGFR2c. The terms “single domain antibody”, “domain antibody”, “Nanobody” in claim 18 each only comprise 3 CDRs of a parental antibody.
The specification discloses a mouse antibody Ab 21, a chimeric antibody thereof, and two humanized antibodies thereof, i.e. Ab hu21-21 and Ab hu21-26 (Examples 2 and 3). Ab hu21-21 comprise all 6 CDRs of mouse antibody Ab 21. Ab hu21-26 comprises all 6 CDRs of Ab 21 with a single mutation G56R in HCDR2. The specification does not disclose any other antibodies comprising less than 6 CDRs of Ab 21 including single domain antibodies, and having the claimed function (binding to FGFR2b and FGFR1b, and having no detectable binding affinity to FGFR2c). Therefore, the breadth of the claims is enormous.
The specification provides one antibody i.e. Ab hu21-26 which comprises all 6 CDRs of Ab 21 with a single mutation G56R in HCDR2. The specification does not provide working examples and guidance on making any other antibodies comprising less than 6 CDRs of parental antibody Ab 21 including any single domain antibodies and having the claimed function.
The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19 24 (CCPA 1970). While it is understood that the absence of working examples should never be the sole reason for rejecting a claims as being broader than an enabling disclosure, the criticality of working examples in an unpredictable art such as antibody engineering is required for practice of the claimed invention.
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). 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 (Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, March 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. Murphy et al. (Journal of Immunological Methods, Vol. 463, Pg. 127-133, 2018), teach that altering amino acid D92 in the complementarity determining region light chain region 3 (CDRL3) of single chain fragment variable (scFv) 2G1 obliterates its capacity to bind to microcystin-leucine-arginine (MC-LR)(Page 130, Section 3.2, paragraph 2) and changing phenylalanine at position 91 to tyrosine caused an increased in binding to MC-LR, compared to the parent clone (Page 131, Column 1, Paragraph 2). The alterations in binding that were observed in these two variants demonstrate the highly influential role of CDRL3 in binding MC-LR. Thus, the state of the art recognized that it would be highly unpredictable that a specific antibody comprising less than all six CDRs of a parental antibody with a desired specificity would retain the antigen-binding function of the parental antibody. Thus, the minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of the parental donor antibody includes six CDRs (i.e. VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3) from parental donor antibody in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function of the parental donor antibody. One of ordinary skill in the art could not predictably extrapolate the teachings in the specification, limited to antibodies that comprise all six CDRs of a parental donor antibody that binds antigen to antibodies that comprise fewer than all six CDRs from the parental donor antibody, wherein the antibodies retain the antigen specificity of the parental donor antibody. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). One of skill in the art would neither expect nor predict the appropriate functioning of the antibodies as broadly as is claimed.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by Paul, Rudikoff and Murphy et al., the lack of guidance and direction provided by applicant, and the absence of working examples for making functional antibodies comprising less than 6 CDRs of a parental antibody, undue experimentation would be required to make/use the claimed invention.
Conclusion
18. No claims are allowed. Claims 1, 4-6, 8-12, 17-18, 22, 24-25, 27, 30, 41 and 52 are rejected. Claim 7 is objected to.
19. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
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/HONG SANG/Primary Examiner, Art Unit 1646