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 3-4, 6-7, 9, 11 are cancelled. Claims 1-2, 5, 8, 10, and 12-25 as filed on 07 January 2024 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 1-2, 5, 8, 10, and 12-25 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 1 is to an isolated anti-TNFR2 antibody that specifically binds an epitope on human TNFR2 where the epitopes comprises or consists of amino acid resides Arg99, Lys108, Glu110, Gly111, Arg113, Leu114, and Asp136 of SEQ ID NO: 83. This provides no limitations on the structure or sequence of the TNFR2 binding antibody.
Claim 2 is to an isolated anti-TNFR2 antibody that comprises HCDR1, 2, and 3 of SEQ ID NO: 1, 7, and 14, respectively with LCDR1, 2, and 3 of SEQ ID NO: 20, 27, and 33. But the claim allows for variation of up to 3 amino acids in each of the six CDRs.
Claim 5 depends from claim 2 and defines the VH and VL of the antibodies that TNFR2 but allows for up to 20% variation without limiting the CDRs of the heavy and light chain.
Claim 8 is to an isolated TNFR2 antibody with the CDR sequences shown in the table below, but includes up to 5 amino acid substitutions in each CDR.
Claim 8 CDR Sequences
HCDR1
HCDR2
HCDR3
LCDR1
LCDR2
LCDR3
SEQ ID NO:
2
8
15
21
28
34
SEQ ID NO:
3
9
16
22
29
35
SEQ ID NO:
4
10
17
23
30
36
SEQ ID NO:
5
11
18
24
31
37
SEQ ID NO:
6
12
19
25
32
38
SEQ ID NO:
6
13
19
26
32
38
Claim 10 depends from claim 8 and defines the VH and VL of the antibodies that TNFR2 but allows for up to 20% variation without limiting the CDRs of the heavy and light chain.
Claims 12-25 do not further limit the sequences of the antibodies.
Summary of Species Disclosed in the original specification
Applicant discloses seven TNFR2 binding antibodies comprising the CDRs shown in the table below. These are shown in Table 2A of the specification with known binding activity in Figures 1-2.
Disclosed TNFR2 Antibodies
HCDR1
HCDR2
HCDR3
LCDR1
LCDR2
LCDR3
SEQ ID NO:
1
7
14
2
27
33
SEQ ID NO:
2
8
15
21
28
34
SEQ ID NO:
3
9
16
22
29
35
SEQ ID NO:
4
10
17
23
30
36
SEQ ID NO:
5
11
18
24
31
37
SEQ ID NO:
6
12
19
25
32
38
SEQ ID NO:
6
13
19
26
32
38
State of the Relevant Art
TNFR2 is a receptor for the cytokine tumor necrosis factor (TNF). TNFR2 is expressed primarily on immune cells and is bound by TNF and LT-α but is primarily activated by TNF. It is believed to be primarily expressed by T cells in a tumor environment where an active immune response is occurring. TNFR2 knockout mice shoed decreased tumor growth (Tam et al. Science Translational Medicine. 11(512):1-15. (2019) (IDS) (page 1 in col 1 in par 2 and col 2 in lines 1-2). Tam teaches multiple antibodies that bind TNFR2 for use in the treatment of cancer (abstract and Figures 1-2).
It has been well established 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). But while this overall structure is shared amongst antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure of each monoclonal antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). The epitope of an antibody does not provide structure or sequence information about the antibody that binds it.
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 Brown et al., J. Immunol., 156(9):3285-91 (1996) (PTO-892). Brown teaches 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).
This is further 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. The field has shown repeatedly over decades that 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).
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. An epitope does not inform one of skill in the art of the structure of the antibody that binds it and a partial structure of only some CDRs or some of the CDR sequences does not provide sufficient information to identify the undefined CDR identity.
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 seven antibodies that bind TNFR2 that have fully defined CDRs of the light and heavy chain. The specification does not disclose how changes to the CDRs would impact binding activity of the seven species disclosed. The art does not provide one of skill in the art with how to change the CDRs of the antibody and maintain binding activity. The specification and art does not provide how one of skill in the art would build CDRs that bind the epitope based only on a defined epitope.
Given the variability encompassed by the genus of antibodies that bind TNFR2 the described species cannot be considered representative of the genus that includes any CDR sequences for claim 1 and multiple variations to CDRs in all other claims.
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 described above the structure in an antibody that provides its binding activity is the set of 6 CDRs. As changes to the amino acids of the CDRs, the CDRs of the disclosed antibodies do not disclose additional antibodies. The epitope of an antibody, no matter how specific, does not provide any structure for the CDRs of an antibody that binds that epitope.
Conclusion:
For all of the reasons presented above, one of skill in the art would not know which of the CDR combinations would meet the structural and functional requirements of the claims. The applicant has not provided a representative number of species for all antibodies that bind the epitope of TNFR2 of claim 1 or the partially defined CDRs of claims 2, 5, 8, 10, and 12-25. The functional structure of an antibody are its 6 CDRs that provide its binding activity based on the sequences of those CDRs, the CDRs of one antibody do not provide one of skill in the art with the functional CDRs of additional antibodies so the variability of the CDRs of the rejected claims mean there is no structure/function correlation, and the disclosed species do not provide written description for additional antibodies. 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.
This rejection could be overcome by limiting the claims to specific combinations
of six CDRs without percent identity or substitutions allowed in the CDRs. The claims can recite less than 100% identity in VH and VL sequences outside of the 6 CDRs.
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 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Faustman (WO 2019094559 A2) (IDS).
Faustman teaches a TNFR2 binding antibody that binds an epitope comprising the amino acids of claim 1 (claim 2 subparts a-c in sequences of these subparts).
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 1-2, 5, 8, 12-17, and 22-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 10-11, and 15-26 of copending Application No. 19146022 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant SEQ ID NO: 1 matches SEQ ID NO: 1 of the reference application, instant SEQ ID NO: 7 matches SEQ ID NO: 2 of reference application, instant SEQ ID NO: 14 matches SEQ ID NO: 3 of the reference application thus teaching the CDRs of the heavy chain of instant claims 2 and 8, and instant SEQ ID NO: 20 matches SEQ ID NO: 4 of the reference application, instant SEQ ID NO: 27 matches SEQ ID NO: 5 of the reference application, and instant SEQ ID NO: 33 matches SEQ ID NO: 6 of the reference application, teaching the CDRs of the light chain of instant claims 2and 8.
Regarding claims 1-2, 8, and 23-25, the reference application recites the HCDRs and LCDRs of an antibody that binds TNFR2 in a method of treating an infectious disease (claim 1). The reference application recites the treatment of HPV as required by instant claim 25 (claim 18). By reciting an antibody of instant claim 2 it recites the epitope of instant claim 1.
Regarding claim 5, reference application SEQ ID NO: 7 matches instant SEQ ID NO: 39 and reference application SEQ ID NO: 16 matches instant SEQ ID NO: 63 (claim 15).
Regarding claim 12, by reciting the antibody of instant claim 2 the antibodies of the reference application would inherently have the binding activity required by instant claim 12.
Regarding claims 13-16, the reference application recites the antibody comprises an Fc fragment, is a full length IgG1 antibody, a chimeric antibody, or an scFv (claim 16).
Regarding claim 22, the reference application recites a pharmaceutical composition (claim 21).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 2 and 18-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 10-11, and 15-26 of copending Application No. 19146022 (reference application) in view of Faustman (WO 2019094559 A2) (IDS).
The recitations of the reference application from the previous double patenting rejection are incorporated here in full.
Instant SEQ ID NO: 1 matches SEQ ID NO: 1 of the reference application, instant SEQ ID NO: 7 matches SEQ ID NO: 2 of reference application, instant SEQ ID NO: 14 matches SEQ ID NO: 3 of the reference application thus teaching the CDRs of the heavy chain of instant claims 2 and 8, and instant SEQ ID NO: 20 matches SEQ ID NO: 4 of the reference application, instant SEQ ID NO: 27 matches SEQ ID NO: 5 of the reference application, and instant SEQ ID NO: 33 matches SEQ ID NO: 6 of the reference application, teaching the CDRs of the light chain of instant claims 2and 8.
Regarding claims 2 and 8, the reference application recites the HCDRs and LCDRs of an antibody that binds TNFR2 in a method of treating an infectious disease (claim 1).
The reference application does not recite a host cell comprising a vector encoding a TNFR2 antibody or a method of producing the antibodies.
These deficiencies are filled by Faustman.
Regarding claims 18-20, Faustman teaches a host cell comprising a vector encoding an antibody that binds the same epitope of the claims (claims 58-70).
Regarding claim 21, Faustman teaches a method of producing the antibody by culturing the vector comprising the vector that encodes a TNFR2 binding antibody (claims 81-83 and page 68 in lines 30-39).
It would have been obvious at the time the application was filed to combine the TNFR2 binding antibody of the reference claim with the method of producing the antibody by host cell comprising a vector that encodes it as taught by Faustman. Faustman teaches a method of producing antibodies that bind the same target as the reference claims. One of skill in the art would have been motivated to use well known in the art methods of producing therapeutic antibodies to produce sufficient antibodies for use in a therapeutic composition. Faustman teaches a method of producing TNFR2 binding antibodies for use in pharmaceuticals. There would have been a reasonable expectation of success as Faustman teaches a straightforward method of producing an antibody for use with antibodies of varying binding activity including binding TNFR2 and the skill level of producing antibodies of specific CDRs, as recited by the reference claims, by producing their nucleic acid sequence from the amino acid sequence and placing them in a vector for production in a host cells was high.
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
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