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 .
Claim Status
Claims 1-18 as filed on 17 January 2024 are pending and under examination.
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 - Claims 4, 6-7, and 15 have amino acid sequences of 4 amino acids and greater without a SEQ ID NO.
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
Sequence are present on pages 15-17, 22, 36-37, 42-43, 76, and 81. Please review the entire specification to make sure no further corrections are needed.
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.
Claim Objections
Claims 1-2, 4, 7, 9, and 11-14 objected to because of the following informalities: have internal periods as part of the letter list in those claims. The periods can be replaced as follows: from “a.” to “a)”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-10, 14, and 16-18 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.
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 it may be satisfied by the 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. “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).
Scope of the Claimed Genus
Claim 1 is to antibody-drug conjugates comprising HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 21, 22, and 23, respectively. These sequences are to DYAMX wherein the X is H or Y; WINXYTGKPTYXXXFXG wherein the X1 is T or A, X2 is A or S, X3 is D or Q, X4 is D or K, and X5 is K or Q; and AVXYGYTMDA wherein the X is F or Y.
The HCDR sequences allow for any mixing and matching of these substitutions within each CDR and mixing and matching of all CDR combinations.
The LCDR 1, 2, and 3 comprise SEQ ID NO: 24, 25, and 26, respectively. These sequences are RXSEDIYSNXA where X1 is A or T, X2 is L or F; XXXRLQD where X1 is S or A, X2 is V or I, and X3 is K or N; and LQGSXFPLT and X is K or N.
The LCDR sequences allow for any mixing and matching of these substitutions within each CDR and mixing and matching of all CDR combinations.
The multitude of HCDR sets can be paired with any of the multitude of LCDR sets.
Claims 2-9, 14, and 16-18 provide no further limitations on the CDRs of the antibodies.
Summary of Species Disclosed in the original specification
Applicant discloses thirteen antibodies in Table 3. Each of the antibodies have a unique but set of 3 HCDRs and 3 LCDRs. Applicant does not disclose the mixing and matching of the HCDR and LCDR sets.
State of the Relevant Art
Claudin 18 isotype 2 (CLDN18.2) is a cancer associated splice variant of the tight junction molecule Claudin 18. CLDN18.2 is a 27.8 kDa transmembrane protein comprising four membrane spanning domains with two small extracellular loops. CLDN18.2 is a highly selective gastric lineage antigen exclusively expressed on short-lived differentiated gastric epithelial cells and not detectable in any other normal human tissue. It is expressed in a number of cancers Sahin (US 20180117174 A1) (IDS) ([0007]).
It has been established for decades in the art that the formation of an intact antigen-binding site in a conventional antibody requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (PTO-892) (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule”, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
Further, the skilled artisan has long recognized that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al., Proc. Nat’l Acad. Sci. USA, 79:1979-83 (1982) (PTO-892). Rudikoff teaches 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. E.g., Abstract. Similarly, Brown et al., J. Immunol., 156(9):3285-91 (1996) (PTO-892), teach that although a single amino acid change in CDR2 of heavy chain of a particular antibody was tolerated, the antibody lost binding upon introduction of two amino acid changes in the same region. Brown, p. 3290 and Tables 1 and 2. Table 1 of Brown shows that even a conservative substitution does not ensure that functionality of the antibody is retained. These older citations are supported my more recent discoveries of why these substitutions change antibody activity. Marvin et. al., Biochemistry, 42(23):7077-7083 (2003) (“Marvin” PTO-892) teaches that changes to the heavy and light chains altered binding affinity (Table 2) with changes to the CDR having large impacts but the changes with the largest impact were from residues in the CDR, but not from ones interfacing with the antigen ( Page 7081 in col 1 “Conclusions and Discussion” and Page 7082 in Figure 4).
The earlier work of Rudikoff and Brown is confirmed by Chiu et al., Antibodies, 8(55):1-80. (2019) (“Chiu” PTO-892). Chiu teaches that the complementarity-determining regions (HCDRs 1-3 and LCDRs 1-3) determine antigen binding requiring specific sequences and orientation of those sequences to properly form tertiary structures that can recognize and bind antigens (Page 4 in 1.2.2 first and last paragraphs and Figure 3). Chiu teaches that antibody modeling with known LCDRs 1-3, HCDR1 and HCDR2 could not predict HCDR3 In the decades since Rudikoff the field has increased understanding of antibody engineering. Structure-Based antibody engineering is unable to predict antibody sequences (Page 6 in 1.2.6, Pages 10-11 in Section 2 in particular second paragraph of page 11). Chiu notes the advancement in antibody engineering but notes it is still not possible to predict the point mutations that would improve affinity in both antibodies and multispecific molecules (Page 51 in lines 6-12). Chiu teaches that antibody-drug conjugates (ADCs) comprise antibodies that act as binding domains and that being in an ADC does not change the binding expectations of the antibody within the ADC (page 32 in Section 3.3 in particular par 1 and 4).
In general, absent at least the conserved structure of the CDRs of the heavy chain and light chain of an antibody, the skilled artisan generally would not be able to visualize or otherwise predict an antibody with a particular set of functional properties would look like structurally.
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire 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.
The specification discloses thirteen antibodies that bind CLDN18.2.
Given the variability encompassed by the genus of mixing and matching of HCDR and LCDR sequences and sets which would each have its own CDR sequences and binding activity; the described species cannot be considered representative of the genus.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activity.
As noted above, the art identifies the CDRs of an antibody as the structure that provides its function. A single change to an amino acid in one CDR changes its binding activity. The disclosure does not provide one of skill in the art with structures that provide the function of the claims except for the thirteen antibodies where all six CDRs are fully defined in their sequences.
Conclusion:
For all of the reasons presented above, one of skill in the art would not know which of the resulting CDR sets would have the function of the claims. Therefore, the skilled artisan would not reasonably conclude that the inventors had full possession of the antibodies as broadly claimed at the time the application was filed. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus. Applicant was not in possession of the invention as claimed.
Examiner notes that claims 11-13 and 15 are not included in this rejection because they are limited to fully defined CDR sets and are the ones disclosed in the application.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17/788, 226 (reference application) in view of Armostrong (WO 2018227023 A1) (PTO-892), Polakis (WO 2014/011520 A1) (PTO-892), and Sahin (US 20180117174 A1) (IDS).
Instant SEQ ID NO: 51 matches SEQ ID NO: 51 of the reference application and instant SEQ ID NO: 46 matches SEQ ID NO: 46 in the reference application. This recites the CDRs of instant claims 1 and 11-12 and its depending claims and the VH and VL of claim 13.
The reference application recites the antibodies of the instant claims in particular in claim 7. The reference application recites the CLDN18.2 antibody of the claims and further recites it binds CLDN18.2 in tumor tissue (claim 1).
The reference application recites the use of the antibody in the treatment of cancer in claim 15.
The reference application does not recite the antibody as part of an antibody-drug conjugate.
This deficiency is filled by Armstrong, Polakis, and Sahin.
Armstrong teaches antibody drug conjugates (ADCs) comprising an antibody that binds a tumor antigen, a linker, and an additional element that works as an immune-modulatory compound. Armstrong teaches numerous antibody targets for use in their ADCs including cldn18.2 ([0004]-[0007]). Armstrong explicitly teaches the substitution of the elements of an ADC by teaching its broad formula on page 2 and claims in particular claims 1-2.
Armstrong teaches the use of its ADCs in combination with additional therapeutics including anthracycline ([0544]).
Regarding claims 4 and 7-8, Armstrong teaches the use of a sortase linker ([0009], claim 18) and further teaches the sequences of sortase linkers of instant claims 4 and 7-8 ([0390]). Armstrong teaches the structures including cleavable linker to a non-cleavable linker to produce an ADC ([0127]). Armstrong teaches THIOMAB and sortase linkers are art equivalents (0515]). Any claim element after a statement of “preferable” is not limiting to the claim and does not need to be recited by the reference claim or taught in the art.
Regarding claim 6, Armstrong teaches the polypeptide linker G4S ([0236]). Armstrong teaches a linker can be flexible, rigid, cleavable, non-cleavable, hydrophilic, or hydrophobic, of comprise segments with different characteristics (0388]). Any claim element after a statement of “preferable” is not limiting to the claim and does not need to be recited by the reference claim or taught in the art.
Armstrong teaches an ADC can produce a stronger immune stimulation and a greater therapeutic window than componenets of the conjugate alone ([0517]).
Polakis teaches immunoconjugates comprising antibodies and drugs as antibody drug conjugates (ADC) (abstract).
Regarding claims 1-2, Polakis teaches the ADC comprises linkers and a toxin and teaches exemplary drugs including anthracycline ([0216] and [0218]). Polakis teaches a number of linkers including EDA ([0215] on page 60).
Regarding claim 3, Polakis teaches the linker comprises a cleavable linker or a spacer elements ([0203]-[0204]).
Regarding claim 8, Polakis teaches the use of a val-cit-PAB linker (page 57).
Regarding claim 9, Polakis teaches the linker and the toxin is covalently linked to the antibody ([010], [0259], and claim 1).
Regarding claim 10, Polakis teaches the ADC components in Figure 11 and ([0223]).
Regarding claim 14, Polakis teaches producing an antibody-drug conjugate by conjugating an antibody to a drug ([0278]-[0280]).
Regarding claim 15, Polakis teaches a pharmaceutical composition comprising and ADC (claim 28) for use in a method of treating cancer that is positive for the antigen the antibody in the ADC binds (claims 30-31) and further teaches an excipient ([076]).
Polakis teaches the 10F4v3 ADC which comprises PNU-159682 and is shown in Figure 4 was effective in 7/9 subjects showing a complete response ([0274]-[0275], and Section B. starting on page 83). Polakis further teaches the ADC comprising thiomab conjugated was less effective version of their ADC ([0294]-[0296]).
Sahin teaches anti-CLDN18.2 antibody-drug conjugates comprises a drug that is a cytotoxic agent including anthracyclines (abstract and [0249]-[0250]). Sahin teaches the anti-CLDN18.2 and the toxin anthracycline ([0249]) for use in a method of treating cancer (claims 1 and 14).
It would have been obvious at the time the application was filed to combine the antibody of the reference claims with the ADC components of Polakis in view of Armstrong and Sahin to produce an ADC comprising the anti-CLDN18.2 antibody of the reference claims, a linker, and an anthracycline toxin. The reference application recites the antibody of the instant claims in a method of treating cancer. One of skill in the art would have been motivated by the teachings of Armstrong to combine the antibody of the reference claim into an ADC to produce the stronger immune therapeutics stimulation and therapeutic window taught by Armstrong for ADCs that bind CLDN18.2. Further, one of skill in the art would have been motivated as Armstrong and Sahin teaches the combination of CLDN18.2 antibodies in ADCs with anthracycline. There would have been a reasonable expectation of success as the reference claims provide an antibody for use in a method of treating cancer and Armstrong and Polakis provide ADCs for use in a method of treating cancer by using an antibody that targets a tumor antigen. Polakis further teaches a reasonable expectation for success as the 10F4v3 ADC comprising the elements of the claims was highly effective in the treatment of subjects showing 7 out of 9 administered had a complete response. Armstrong further supports an expectation of success by teaching the ability to substitute elements of its ADC including the antigen target of its ADC.
Regarding the sortase linker or cleavable required by claims 4 and 7-8, it would have been obvious at the time the application was filed to substitute the thiomab linker of the ADC comprising the antibody of the reference application and the ADC of Polakis with the sortase cleavable linker of Armstrong to produce an ADC comprising the antibody of the reference application linked by a sortase linker of Armstrong with the anthracycline of Polakis. One of skill in the art would have been motivated to improve the THIOMAB comprising ADC of Polakis with the substitution of a different linker. Armstrong teaches THIOMAB and sortase linkers are art equivalent making their substitution obvious. There would have been a reasonable expectation of success as they are art equivalents as linkers used in ADCs for use in a method of treating cancer.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCESCA EDGINGTON-GIORDANO whose telephone number is (571)272-8232. The examiner can normally be reached Mon - Fri 8:00 - 5:00.
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643