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 2-28, 30-60, 64, 66, 68, 70, 72, 74, 76, 78, 80-82,84-90, 92-105, 107-117, 119-122, 124-131, 133-142, and 144-152 are cancelled. Claims 1, 29, 61-63, 65, 67, 69, 71, 73, 75, 77, 79, 83, 91, 106,118, 123, 132, and 143 as filed on 11 March 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:
Claims 1, 21, and 69 recite SEQ ID NO: 10 and 26 which are 3 amino acids in length. These sequences are skip sequences under ST26. They must be replaced by the sequences as amino acids.
Claim Objections
Claims 123, 132, and 143 objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent clam. See MPEP § 608.01(n). Accordingly, the claims not been further treated on the merits.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 29, 61-63, 65, 67, 69, 71, 73, 75, 77, 79, 83, 91, 106, and 118are 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.
Claims 1, 29, and 61 recite SEQ ID NO: 10 and 26. The sequence listing is under ST26 and these sequences are 3 amino acids in length. SEQ ID NO: 10 and 26 are skipped do so the use of these SEQ ID NOs in the claims do not incorporate an amino acid sequence making them indefinite. The depending claims do not correct this.
The claims were examined using the amino acids of SEQ ID NO: 10 and 26 in Figures 2B and 3A which means SEQ ID NO: 10 was examined as EDN and SEQ ID NO: 26 was examined as DVS.
Regarding claims 1, 29, and 61, the claims all recite a parenthetical after each “SEQ ID NO:” of “( . . . with one, two, or three amino acid additions, deletions, or substitutions)”. This renders the claim indefinite because it is unclear whether the limitations within the parenthetical is preferred example –and therefore not limiting—or is part of the claimed invention. The depending claims inherit this issue by depending from these claims and not correcting the indefiniteness.
Regarding claim 118, the claim recites “an antigen binging domain” which is not a term defined in the specification or the art. For the purposes of prosecution and examination the claim and those depending from it were examined as reciting “an antigen binding domain”
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, 29, 61-63, 65, 67, 69, 71, 73, 75, 77, 79, 83, 91, 106, and 118, 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
Base claims 1, 29, and 61 are directed to antibodies or antigen binding fragments comprising either a variable heavy domain alone or a heavy domain and light domain; subparts (i) and (ii) require a heavy and light chain but only partially define the CDRs of the light or heavy chain allowing for up to 3 substitutions, deletions, or additions in each CDR of the heavy or light chains; subparts (iii)-(xi) only partly define the heavy chain allowing for up to 3 substitutions, deletions, or additions in each of the three CDRs of the heavy chain. Subparts (iii)-(xi) allow for the antibodies to be traditional antibodies of a heavy and light chain and provide no limitations on the CDRs of the light chains. The claims are to a functional antigen binding domain but do not require a specific antigen or epitope.
Claim 62 requires the antibody binds SEQ ID NO: 273 or 274 but provides no additional structure or sequence for the antibodies of the claims. These are sequences for PSMA (Figure 1 and page 2 in lines 13-20 of the instant specification).
Claims 63, 65, 67, 69, 71, 73, 74, 75, 77, and 79 are each limited to a single subpart of claim 61, but does not further limit the only partially defined antibodies of the subparts of claim 61.
Claim 83 requires the same partially defined binding domains of claims 1, 29, and 61 are part of a CAR but does not further limit the binding domain sequence or structure.
Claims 91, 106, and118, do not provide any further limitations for the sequence or structure of the CDRs of the antibodies of the claims.
Summary of Species Disclosed in the original specification
Applicant discloses 2 traditional antibodies with fully defined CDRs of the heavy and light chain where the heavy and light chain each comprise 3 CDRs and 9 variable heavy or VH antibodies that comprise 3 fully defined CDRs.
The 2 traditional antibodies are shown to bind the target PSMA when in an antibody or antigen binding domain comprising both the heavy and light chain with fully defined CDRs.
The 9 VH antibodies are shown to bind PSMA when in an antibody or antigen binding domain comprising a variable heavy chain alone with all three fully defined CDRs.
Heavy Chain
Light Chain
SEQ ID NO:
CDR1
CDR2
CDR3
CDR1
CDR2
CDR3
T5-H10
1
2
3
9
10 (EDN)
11
A4-D7
17
18
19
25
26 (DVS)
27
Z4-D2
33
34
35
Z4-D2-F1a
41
42
43
Z1b5p-D1
49
50
51
W5-A4
57
58
59
W5-A4-D3
65
66
67
W5-A4-B7
73
74
75
W5-4mut
81
82
83
12H-D5
89
90
91
12H-E2
97
98
99
State of the Relevant Art
Prostate Specific Membrane Antigen (PSMA) is a type II transmembrane protein encoded by the FOLHI gene in humans. In humans it consists of a 19 amino acid cytoplasmic comina, a 24 amino acid transmembrane potion, and a 707 amino acid extracellular portion. PSMA is expressed on prostrate epithelium tissue and is upregulated in prostate cancer and the neovasculature of solid tumors. It is a known target using antibodies, ADCs, and CARs for treating cancer (Van Schooten (WO 2020206330 A1) (IDS) (abstract and [0002]-[0003])).
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 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 a traditional 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 2 traditional antibodies with fully defined CDRs in the heavy and light chain that bind PSMA and 9 heavy chain antibodies with 3 fully defined in the heavy chain that also bind PSMA.
Claims 1, 29, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 83, 91, 106, and 118 are to an antibody or antigen binding domain with no defined antigen or epitope and only partially defined CDRs. The genus of these claims would be to an antibody that binds any target with the very limited sequence requirements of the claims. This highly variable genus cannot be represented by 11 species as the ability to substitute, add, or delete multiple amino acids from each CDR would change the binding activity of the antibody.
Claim 62 requires a binding target of instant SEQ ID NO: 273 or 274, this limitation does not overcome the issue of a representative number of species as the epitope of an antibody does not change that the description of an antibody by its CDRs does not provide written description on additional antibodies that bind its same target.
The 11 disclosed species cannot be considered representative of antibodies with variable CDRs with or without a required antigen.
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 of a traditional antibody or 3 CDRs for a heavy chain antibody. As changes to the amino acids of the CDRs change its function, the CDRs of the disclosed antibodies do not disclose additional antibodies. The epitope of an antibody or activity upon binding a target, 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 of the claims would meet the structural and functional requirements of the claims. The applicant has not provided a representative number of species for all antibodies, whether they bind PSMA or not, as an antibody does not provide written description for variation to its CDRs. The functional structure of an antibody are its CDRs which provide its binding activity. The variation of CDRs allowed in the claims prevents a structure/function correlation. The claims then do not have a representative number of species or a structure/function correlation for the variable antibodies or antigen binding fragments of the claims.
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.
To limit the claims to antibodies applicant has shown possession of the claims would need to clearly state if the antibody in the subpart is a traditional antibody Examiner notes that the fully defined sequences disclosed by the applicant appear to be free of the art.
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 1, 29, 61, and 69 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Teige (US9266952B2) (PTO-892).
Regarding claims 1, 29, 61, and 69, Teige teaches an antibody comprising SEQ ID NO: 9 which matches with no more than 3 substitutions/additions/deletions in the CDR sequences of a fusion of instant SEQ ID NO: 57 to 58 to 59, shown below (abstract and Figure 6).
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Regarding claim 123, Teige teaches the antibody as part of a pharmaceutical composition (page 9 in lines 20-25).
Claims 1, 29, 61, 71, 73, and 91 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Siu ( WO2007011941-A2) (PTO-892).
Regarding claims 1, 61, and 71, Siu teaches a VH of SEQ ID NO: 12 which matches with no more than 3 substitutions/additions/deletions in the CDR sequences of a fusion of instant SEQ ID NO: 65 to 66 to 67, shown below (abstract, claims 1-8).
Regarding claim 91, Siu teaches bispecific antibodies that have antibodies that are linked (page 29 in lines 13-17).
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Regarding claims 61 and 73, the fusion of SEQ ID NO: 73, 74, and 75 with allowable variation is in Siu’s SEQ ID NO: 14, shown below.
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Regarding claim 123, Siu teaches the antibody as part of a pharmaceutical composition (page 9 in lines 20-25).
Claims 1, 29, 61, 83, 106, 118, 123, and 132 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Rosenthal (US 11174313 B2) (PTO-892).
Rosenthal teaches antibodies and antigen-binding fragments (abstract) including ones that comprise SEQ ID NO: 367 which matches with no more than 3 substitutions/additions/deletions in the CDR sequences of a fusion of instant SEQ ID NO: 65 to 66 to 67, shown below (abstract and col 443).
Regarding claim 83, Rosenthal teaches a CAR comprising the binding domains of its invention (col 61 in lines 5-10).
Regarding claim 106, Rosenthal teaches a host cell comprising a vector that comprises a nucleic acid that encodes the antibodies of their invention (claims 12-14).
Regarding claims 118 and 123, Rosenthal teaches ADCs and pharmaceutical compositions (col 147 in lines 14-30).
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Regarding claim 123, Rosenthal teaches a pharmaceutical composition comprising the antibodies of the instant application (col 53 in lines 20-26).
Regarding claim 132, Rosenthal teaches a method of treating cancer (claims 15-16) and teaches that subjects are mammals (col 185 in lines 42-47).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 29 and 143 are rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal (US 11174313 B2) (PTO-892) and Logtenberg (US 20180142003 A1) (PTO-892).
Regarding claim 29, Rosenthal teaches antibodies and antigen-binding fragments (abstract) including ones that comprise SEQ ID NO: 367 which matches with no more than 3 substitutions/additions/deletions in the CDR sequences of a fusion of instant SEQ ID NO: 65 to 66 to 67, shown below (abstract and col 443).
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Rosenthal teaches CD33 binding antibody is used in a bispecific or multivalent antibody (claim 9).
Rosenthal does not teach the antibodies of its invention binds PSMA.
This deficiency is filled by Logtenberg.
Logtenberg teaches bispecific antibodies that bind CD33 and PSMA (claims 20-21). Logtenberg teaches the antigens targeted are of interest in multiple diseases (claims 18-21).
It would have been obvious at the time the application was filed to substitute the generic target of the bispecific antibody of Rosenthal with the PSMA binding of Logtenberg to produce the bispecific antibody that has the sequence requirements of the instant claims and binds PSMA. One of skill in the art would have been motivated by the teachings of Logtenberg as producing compositions that bind two targets Logtenberg teaches as useful in binding markers of a variety of diseases. There would have been a reasonable expectation of success as Logtenberg teaches bispecific binding of PSMA and CD33 and Rosenthal teaches the use of their antibodies in a bispecific antibody.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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