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 1-32 are cancelled. Claims 33-53 as filed on 05 September 2023 are pending and under examination.
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 33-53 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.
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 33 is to an anti-CLDN6 antibodies comprising a VH and VL wherein the VH comprises 3 HCDRs with variable sequences allowing for one or more mutations of the HCDRs and the VL comprises 3 LCDRs with variable sequences allowing for one or more mutations of the LCDRs.
Claim 34 subparts 2-8 limits only the heavy or light chain allowing for unlimited variation in the VH or VL.
Claim 35 allows percent identity and substitution of amino acids of the VH and VL sequences allowing for variation in the CDRs of these VH and VL.
Claims 36-53 does not further limit the CDRs of the VH and VL of the antibodies.
None of the claims are limited to fully defined CDRs in the VH and VL.
Summary of Species Disclosed in the original specification
Applicant discloses the following anti-CLDN6 antibodies: 15H2 comprising HCDR1, 2, and 3 of SEQ ID NO: 3, 4, and 5, respectively with LCDR 1, 2, and 3 of SEQ ID NO: 6, 7, and 8, respectively; 9H3 comprising HCDR1, 2, and 3 of SEQ ID NO: 13, 14, and 15, respectively with LCDR 1, 2, and 3 of SEQ ID NO: 16, 17, and 18, respectively; 7008-03 comprising HCDR1, 2, and 3 of SEQ ID NO: 13, 23, and 15, respectively with LCDR 1, 2, and 3 of SEQ ID NO: 24, 17, and 18, respectively ([0217]).
State of the Relevant Art
Claudins are cell membrane proteins of approximately 23 kD with four transmembrane domains. There are 24 known members in humans and mice including CLDN6. Claudins have unique expression pattern depending on epithelial cell type. Human CLDN6 has high expression in cancer (US 20110059469 A1) (IDS) ([0002]-[0003]). CLDN6 binding antibodies are known for staining CLDN6 in human cancer and for use in treating cancer ([0009]-[0011]).
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 three antibodies that bind CLDN6.
Given the variability encompassed by the genus of anti-CLDN6 antibodies comprising varying CDR sequences the described species therefore cannot be considered representative of the genus. An antibody as defined by its CDRs provides only the binding activity of that antibody not of any variation to those sequences.
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 three 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 countless other compositions encompassed by the claims that meet the highly general structural requirements of the claims would also possess the required functional activity. Therefore, the skilled artisan would not reasonably conclude that the inventors had full possession of compositions 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.
Claim 51 is 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 a method of treating cancer using the anti-CLDN6 antibodies comprising the VH and VL of SEQ ID NO 1 and 2, the VH and VL of SEQ ID NO: 9 and 10, or VH and VL of SEQ ID NO: 11 and 12, does not reasonably provide enablement for treatment with any anti-CLDN6 antibodies or of preventing cancer with any anti-CLDN6 antibodies. 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 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 in In re Colianni, 195 USPQ 150 (CCPA 1977) and have been adopted by the Board of Patent Appeals and Interferences in Ex Parte Forman, 230 USPQ 546 (BPAI 1986). Among these factors are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack thereof in the art,
4. the breadth of the claims,
5. the amount of direction or guidance present, and
6. the presence or absence of working examples.
The following is an analysis of these factors in relationship to this application.
Breadth of Claims
The claim is to a method of preventing or treating a tumor by administering an anti-CLDN6 antibody.
Guidance/Working Examples
Applicant discloses the following anti-CLDN6 antibodies: 15H2 comprising HCDR1, 2, and 3 of SEQ ID NO: 3, 4, and 5, respectively with LCDR 1, 2, and 3 of SEQ ID NO: 6, 7, and 8, respectively; 9H3 comprising HCDR1, 2, and 3 of SEQ ID NO: 13, 14, and 15, respectively with LCDR 1, 2, and 3 of SEQ ID NO: 16, 17, and 18, respectively; 7008-03 comprising HCDR1, 2, and 3 of SEQ ID NO: 13, 23, and 15, respectively with LCDR 1, 2, and 3 of SEQ ID NO: 24, 17, and 18, respectively ([0217]).
The applicant discloses the binding to tumor by the antibodies (Examples 5-7).
The applicant does not disclose any prevention of cancer with an anti-CLDN6 antibodies.
State of the Art/Predictability
The nature of the invention is such that the composition of the instant claim
must have a therapeutic benefit and be able to prevent cancer
from forming in a patient, much like a vaccine. The art teaches that a vaccine must be prophylactic (Stedman's Medical dictionary, 2012, page 11760, in col 1 bullets 9-10)(PTO-892). The specification does not provide any teachings of the prophylaxis of cancers, how to determine the individuals who will develop one or more of the cancers of the claims, nor how to effectively prevent said particular diseases before occurrence. Thus, one of skill in the art would not be able to use the composition of the invention as a preventing vaccine without undertaking to determine how to select for individuals who will develop the diseases before the said disease occurs in the individual. An effective therapeutic protocol for the treatment or prevention of the formation of any disease is subject to a number of factors, which enter the picture beyond simply the administration of the antibody claimed.
Predicting whether an individual is at risk for developing a disease is a very
unpredictable art. Several factors play a role including, genetic makeup, environmental
factors, age, diet, etc. Therefore, given the unpredictability of prevention and the unpredictability and the broad scope of the claims, undue experimentation would be
required to use the claimed antibody as a method for preventing cancer.
One of skill in the art would not be able to make or use the method of preventing cancer with an anti-CLDN6 antibody.
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.
Claims 33-43 and 46-53 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Aburatani (US 20110059469 A1) (IDS).
All claims allow for unlimited substitution and only partial defined sequences of the CDRs. The sequences are then not required to teach the claims.
Regarding claims 33-34, Aburatani teaches anti-CLDN6 antibodies (claims 1-6).
Regarding claim 35, subpart (a)(ii) and b(v) allows for unlimited substitution of the VH and VL sequences making the claim have no required sequences in the antibodies of the claims.
Regarding claim 36, Aburatani teaches the antibody can be a Fab ([0134]).
Regarding claims 37-39 and 48, Aburatani teaches cells that express vectors that have nucleic acids encoding the anti-CLDN6 antibodies ([0058]).
Regarding claim 40, Aburatani teaches the purification of antibodies from the cultured cells encoding the anti-CLDN6 antibodies ([0076]).
Regarding claim 41, Aburatani teaches a bispecific antibody that binds CLDN6 and a further target ([0140]).
Regarding claim 42, Aburatani teaches the antibodies as antibody-drug conjugates ([0012]).
Regarding claim 43, Aburatani teaches pharmaceutical compositions comprising the antibody and acceptable carriers ([0149]).
Regarding claims 49-51, Aburatani teaches the administration of the antibodies to subjects with cancer and the inhibition of the tumor by its administration ([0143]-[0148]).
Regarding claims 52-53, Aburatani teaches the diagnosis of cancer by use of detecting CLDN6 with the antibody ([0153]-[0159]).
Claims 33 and 44-48 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Escarpe (WO 2016 073649) (IDS).
Regarding claims 33 and 45, Escarpe teaches antibodies that binds CLDN6 and CARs that bind CLDN6 (abstract and page 2 in lines 10-30).
Regarding claim 44, Escarpe teaches kits for use in treatment of patients (page 6 in lines 20-24).
Regarding claims 46-48, Escarpe teaches a host cell comprising a vector of the nucleic acids that encode the CARs of the invention (claims 9-18).
Conclusion
No Claims allowed.
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/F.E./Examiner, Art Unit 1643
/Meera Natarajan/Primary Examiner, Art Unit 1643