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 .
DETAILED ACTION
Response to Amendment and Arguments
The Amendment filed on 8/21/2008 in response to the previous Non-Final Office Action (2/22/2008) is acknowledged and has been entered.
Claims 1-33, 35-121, 123-126, 132, 137, 139 and 146-148 have been cancelled.
Claims 34, 122, 127-131, 133-136, 138, and 140-145 are pending and under consideration for a protein comprising a scFv to tumor antigen and a Fab to NKG2D antigen.
Information Disclosure Statement
The information disclosure statement (s) (IDS) submitted on 9/2/2025 are/is considered by the examiner and initialed copies/copy of the PTO-1449 are/is enclosed.
Terms used in this application and applicant’s argument:
Bispecific antibody: an antibody having two binding arms: one binds NKG2D and one bind tumor associated antigen (TAA).
TriNKET: A bispecific antibody comprising one arm to NKG2D, one arm binding TAA, and constant domains bind CD16 (Fc receptor).
F3-TriNKET: The binding arm to NKG2D is scFv and the binding arm to TAA is Fab.
F’3-TriNKET: The binding arm to NKG2D is Fab and the binding arm to TAA is scFv.
Rejection Maintained and Response to Arguments
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 obviousness-type 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); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but an examined application claim not is patentably distinct from the reference claim(s) because the examined 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).
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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
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 (MPEP 9th Ed, Feb 2023).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Over Patents:
Claims 34, 122, 127-131, 133-136, 138, and 140-145 remain and are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over:
Claims 1-14 of U.S. Patent 11,884,733 (original application 16/967216);
Claims 1-16 of U.S. Patent 11,939,384 (original application 18/501413);
Claims 1-18 of U.S. Patent 12,264,200 (original application 18/501427);
Claims 1-8 of U.S. Patent 12,129,300 (original application 18/501419).
Although the conflicting claims are not identical, they are not patentably distinct from each other because all sets of claims encompass the same antibodies having the same antigen binding fragment and structure. The claims in the patents would anticipate and obvious over the instant claims.
Claim amendment:
Base claim 34 of the present application has been amended from “A protein comprising (a), (b) and (c)” to “A protein consisting essentially of (a), (b) and (c)”…..
The transitional phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976).
There is no clear definition provided in the specification for ingredients are steps that would materially affect the product. Therefore, the “consisting essentially of” language in the claim is being interpreted as “comprising”. See the MPEP § 2111.03.
The instant claims are amended and drawn to
A protein consisting essentially of:
(a) a single-chain variable fragment (scFv) that binds a tumor-associated antigen;
(b) a Fab that binds NKG2D, the Fab comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR1, CDR2, and CDR3 amino acid sequences set forth in SEQ ID NOs: 319, 96, and 339, respectively, wherein the X in SEQ ID NO:339 is M, L, I, V, Q, or F, and
the light chain variable domain comprises CDR1, CDR2, and CDR3 amino acid sequences set forth in SEQ ID NOs: 99, 100, and 101, respectively; and
(c) a first antibody constant domain and a second antibody constant domain that form a heterodimer that binds CD 16, wherein the scFv is linked to the N-terminus of the first antibody constant domain via a hinge sequence, and the Fab is linked to the N-terminus of the second antibody constant domain,
wherein the VH is at least 98-99% sequence identity to SEQ ID NO: 337(claim 142-143);
wherein the tumor associated antigen is HER2 (claim 138)
…….
The claims of ‘733 patent are drawn to
An antigen-binding site that binds NKG2D, comprising
an antibody heavy chain variable domain comprising a complementarity-determining region 1 (CDR1) sequence represented by the amino acid sequence of SEQ ID NO:48, a complementarity-determining region 2 (CDR2) sequence represented by the amino acid sequence of SEQ ID NO:30, and a complementarity-determining region 3 (CDR3) sequence represented by the amino acid sequence of SEQ ID NO:78, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO: 80, or SEQ ID NO:82; and
an antibody light chain variable domain comprising a CDR1 sequence identical to the amino acid sequence of SEQ ID NO:32, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO:33, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:34.
A protein comprising the antigen-binding site according to claim 1 and an additional antigen-binding site, which is a tumor associated antigen that is HER2, EpCAM…..
The claims of ‘384 patent are drawn to
A method of providing a cancer immunotherapy for treating a cancer in a patient in need thereof, the method comprising administering to the patient an effective amount of a protein comprising an antigen-binding site that binds NKG2D and an additional antigen-binding site that binds a tumor-associated antigen expressed by the cancer, wherein the antigen-binding site that binds NKG2D comprises:
an antibody heavy chain variable domain comprising a complementarity-determining region 1 (CDR1) amino acid sequence of SEQ ID NO: 48, a complementarity-determining region 2 (CDR2) amino acid sequence of SEQ ID NO: 30, and a complementarity-determining region 3 (CDR3) amino acid sequence of SEQ ID NO: 78, 74, 76, 80, or 82; and
an antibody light chain variable domain comprising a CDR1 amino acid sequence of SEQ ID NO: 32, a CDR2 amino acid sequence of SEQ ID NO: 33, and a CDR3 amino acid sequence of SEQ ID NO: 34, wherein the additional antigen-binding site comprises an antibody heavy chain variable domain, wherein the antibody heavy chain variable domain of the antigen-binding site that binds NKG2D is present on a first polypeptide that further comprises a first antibody constant region, and the antibody heavy chain variable domain of the additional antigen-binding site is present on a second polypeptide that further comprises a second antibody constant region, and wherein the first antibody constant region and the second antibody constant region form a complex that binds CD16,
wherein the VH domain having 95% sequence identity to SEQ ID NO: 85 and VL domain having 95% sequence identity to SEQ ID NO: 8.
The claims of ‘200 patent are drawn to
An antigen-binding site that binds NKG2D, comprising: an antibody heavy chain variable domain comprising a complementarity-determining region 1 (CDR1) amino acid sequence of SEQ ID NO: 48, a complementarity-determining region 2 (CDR2) amino acid sequence of SEQ ID NO: 30, and a complementarity-determining region 3 (CDR3) amino acid sequence of SEQ ID NO: 71; and an antibody light chain variable domain comprising a CDR1 amino acid sequence of SEQ ID NO: 32, a CDR2 amino acid sequence of SEQ ID NO: 33, and a CDR3 amino acid sequence of SEQ ID NO: 34,
protein comprising the antigen-binding site of claim 1 and an additional antigen-binding site, that is tumor associated antigen (claims 5-6).
The claims of ‘300 patent are drawn to
A method of providing a cancer immunotherapy for treating a cancer in a patient in need thereof, the method comprising administering to the patient an effective amount of a protein comprising an antigen-binding site that binds NKG2D and an additional antigen-binding site that binds a tumor-associated antigen expressed by the cancer, wherein the antigen-binding site that binds NKG2D comprises: an antibody heavy chain variable domain comprising a complementarity-determining region 1 (CDR1) amino acid sequence of SEQ ID NO: 48, a complementarity-determining region 2 (CDR2) amino acid sequence of SEQ ID NO: 30, and a complementarity-determining region 3 (CDR3) amino acid sequence of SEQ ID NO: 71; and an antibody light chain variable domain comprising a CDR1 amino acid sequence of SEQ ID NO: 32, a CDR2 amino acid sequence of SEQ ID NO: 33, and a CDR3 amino acid sequence of SEQ ID NO: 34, wherein the additional antigen-binding site comprises an antibody heavy chain variable domain, wherein the antibody heavy chain variable domain of the antigen-binding site that binds NKG2D is present on a first polypeptide that further comprises a first antibody constant region, and the antibody heavy chain variable domain of the additional antigen-binding site is present on a second polypeptide that further comprises a second antibody constant region, and wherein the first antibody constant region and the second antibody constant region form a complex that binds CD16.
All the reference Patents are from the same family, which have the same sequence identifiers.
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The reference patents above and instant application encompass
The same antigen binding domain to tumor associated antigen(s) TAA, and
The same antigen binding domain) to NKG2D as sequence alignments.
Summaries of the sequence similarity recited in the claims between the instant application and the reference patents:
VL domain:
The Instant VLCDR1-3 have the identical sequence as the CDRs within the VL domain of all reference patents as sequence alignment:
QY=fuse instant SEQ ID NOs: 99 to 100 to 101 (VLCDR1-3)
Qy 1 RASQGISSWLA---------------AASSLQS--------------------------- 18
||||||||||| |||||||
Db 24 RASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDF 83
Qy 19 -----QQGVSFPRT 27
|||||||||
Db 84 ATYYCQQGVSFPRT 97
which has identical sequence as VLCDR1-3: SEQ ID NOs: 32, 33, and 34 or VL of SEQ ID NO: 8 of reference patents (also see SCRE or SCV for details).
VH domain:
The instant VHCDR1-2 have identical sequences as VHCDR1-2 of the reference patents while the instant VHCDR3 contain X at location of amino acid no 4, wherein X= M, L, I, V, Q or F:
QY= fuse instant VHCDR1-3 = SEQ ID NOs: 319 to 96 to 339
Qy 1 SYSMN--------------SISSSSSYIYYADSVKG------------------------ 22
||||| |||||||||||||||||
Db 31 SYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAED 90
Qy 23 --------GAPXGAAAGWFDP 35
|||||||||||||
Db 91 TAVYYCARGAPXGAAAGWFDP 111
Wherein the amino acid X at position 4 of VHCDR3, SEQ ID NO: 339, of the instant application matches to VHCDR3 for Patent No. ‘733 and ‘384 (see claim 1 of both patents for details):
SEQ ID NO: 78, aa at No 4 is I (GAPIGAAAGWFDP)
SEQ ID NO: 74, aa at No 4 is Q (GAPQGAAAGWFDP)
SEQ ID NO: 76, aa at No 4 is L (GAPLGAAAGWFDP)
SEQ ID NO: 80, aa at No 4 is F (GAPLGAAAGWFDP)
SEQ ID NO: 80, aa at No 4 is V (GAPVGAAAGWFDP), and
VHCDRs for Patent No. ‘200 and ‘300:
SEQ ID NO: 71, aa at No 4 is M (GAPMGAAAGWFDP)
Accordingly, the claims of all the reference patents having the identical VLCDR1-3 and VHCDR1-3 as well as VH and VL as the instantly claimed antibody as above (also see SCORE or SCV for details).
The scFv binding to tumor associated antigen including HER2 of the instant claims is also recited in the reference patents. All sets of the claims also recite first and second Fc or constant regions together binding to Fc receptor CD16.
Thus, the instant claimed invention (a protein/antibody) and reference patents encompass the same antigen binding fragments (domains) to a tumor associated antigen (first arm) and to NKG2D (second arm) with the identical CDR sequences and the same antibody format F’3-TriNKET (or F’3-format), wherein anti-NKG2D is Fab and anti-TAA is scFv (see figure 1A, page 10 of last Office action)
For the reasons, here the NSDP rejections are maintained and made again.
Response to applicant’s argument:
Applicant provides the following arguments, and each is responded accordingly:
I. Claim construction
I.A Construction of the instant claims
Independent claim 34 of the instant application is amended to
34. A protein consisting essentially of:
(a) a single-chain variable fragment (scFv) that binds a target antigen;
(b) a Fab that binds NKG2D, the Fab comprising a heavy chain variable
domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR1, CDR2, and CDR3 amino acid sequences set forth in SEQ ID NOs: 319, 96, and 339, respectively, wherein the X in SEQ ID NO:339 is M, L, I, V, Q, or F, and the light chain variable domain comprises CDR1, CDR2, and CDR3 amino acid
sequences set forth in SEQ ID NOs: 99, 100, and 101, respectively; and
(c) a first antibody constant domain and a second antibody constant domain
that form a heterodimer that binds CD 16,
wherein the scFv is linked to the N-terminus of the first antibody constant
domain via a hinge sequence, and the Fab is linked to the N-terminus of the second
antibody constant domain.
Applicant submits that amended claim 34 is directed to a protein consisting essentially of an antigen-binding site that binds a target antigen, an antigen-binding site that binds NKG2D, and a CD 16-binding heterodimer of antigen constant domains. The CDR sequences of the antigen-binding site that binds NKG2D are specifically recited. Such a protein is referred to herein as a "TriNKET" for conciseness. Claim 34 further specifies that the antigen-binding site binding the target antigen is in an scFv, the antigen-binding site binding NKG2D is in a Fab, and both the scFv and the Fab are linked to the N-terminus of the dimer of antibody constant domains. Such a format is referred to in the instant application as "F3’ format" or F3’-TriNKET," in contrast to "F3 format" or "F3 -TriNKET" in which the antigen-binding site binding the target antigen is in a Fab and the antigen-binding site binding NKG2D is in an scFv (bridging page 7-8).
In response, the Office’s comment regarding with the claims amendment from “comprising” to “consisting essentially of” is set forth above. Thus, “consisting essentially of” language of claim 34 is still read and interpreted as “comprising”.
The Office agrees that the instantly claimed antibody has the structure of F3’ format or F3’-TriNKET.
I.B. Construction of the reference claims
I.B.1 The reference claims
'733 Patent includes 14 claims. Certain claims, including claims 1 and 3 discussed by the Office Action, are reproduced below.
1. An antigen-binding site that binds NKG2D, comprising an antibody heavy chain variable domain comprising a complementarity-determining region 1 (CDR1) sequence represented by the amino acid sequence of SEQ ID NO:48, a complementarity-determining region 2 (CDR2) sequence represented by the amino acid sequence of SEQ ID NO:30, and a complementarity-determining region 3 (CDR3) sequence represented by the amino acid sequence of SEQ ID NO:78, SEQ ID NO:74, SEQ ID NO:76, SEQ TD NO: 80, or SEQ ID NO:82; and an antibody light chain variable domain comprising a CDR1 sequence identical to the amino acid sequence of SEQ ID NO:32, a CDR2 sequence identical to the amino acid sequence of SEQ TD NO:33, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:34.
3. A protein comprising the antigen-binding site according to claim 1 and an
additional antigen-binding site.
6. The protein according to claim 3, wherein the additional antigen-binding site comprises an antibody heavy chain variable domain; and wherein the antibody heavy chain variable domain of the antigen-binding site that binds NKG2D is present on a first polypeptide further comprising a first antibody constant region, and the antibody heavy chain variable domain of the additional antigen-binding site is present on a second polypeptide further comprising a second antibody constant region.
Applicant further reproduces the claims of the applications discussed in the last Office including:
claim 1 of ‘384 patent;
claims 1, 5, and 7 of ‘200 patent;
claims 1 of ‘300 patent,
(see page 9-10 of Remarks or the claims in the patents for details).
I.B.2. Legal Principles for Claim Construction
As provided in the MPEP, the USPTO employs the "broadest reasonable interpretation" standard for claim construction:
The Patent and Trademark Office ("PTO") determines the scope of claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction "in light of the specification as it would be interpreted by one of ordinary skill in the art.
The MPEP further explains:
Under a broadest reasonable interpretation (BRI), words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the relevant time.
Though understanding the claim language may be aided by explanations contained in the written description, it is important not to import into a claim limitations that are not part of the claim. For example, a particular embodiment appearing in the written description may not be read into a claim when the claim language is broader than the embodiment.
Specifically, the MPEP cites federal appellate court decisions in which "the court expressly rejected the contention that if a patent describes only a single embodiment, the claims of the patent must be construed as being limited to that embodiment."10 More recent cases also confirmed that "although the specification often describes very specific embodiments of the invention, we have repeatedly warned against confining the claims to those embodiments."""Even when the specification describes only a single embodiment, the claims of the patent will not be read restrictively unless the patentee has demonstrated a clear intention to limit the claim scope using 'words or expressions of manifest exclusion or restriction.
In response, the examiners in the Office of PTO use MPEP as guidances for examining all US Patent applications including the instant application.
I.B.3. Construction of the Reference Claims
Certain Reference Claims are directed to a TriNKET protein, which includes an antigen- binding site that binds NKG2D, an additional antigen-binding site, and a CD 16-binding heterodimer of antigen constant regions. The term "antigen-binding site" is defined in the specification of the Reference Patents to mean "the part of an immunoglobulin molecule that participates in antigen binding."13 The definition does not further limit the antigen-binding site by format. Besides identifying the structural components, the Reference Claims recite specific CDR sequences of the antigen-binding site that binds NKG2D. As pointed out by the Office Action, the CDR sequences are also claimed by the Reference Patents.
Applicant submits that none of the Reference Claims specifically identify the format of a TriNKET. For example, the Reference Claims are silent on both (i) the format of the antigen- binding site that binds NKG2D and (ii) the format of the additional antigen-binding site. These claims are also silent on how these antigen-binding sites link to the dimer of antigen constant regions. Following the MPEP, Applicant respectfully submits that, under the broadest reasonable interpretation, the Reference Claims should allow the NKG2D-binding site and the additional antigen-binding site to each take various formats and to link to the dimer of antibody constant regions in various orientations. A genus of such TriNKETs includes numerous species, as described in the amendment and response filed on January 29, 2025.
Applicant submits that nothing in the specification of the '733 Patent would be recognized by the skilled person as being inconsistent with this claim construction. Nor did Applicant indicate, in either the specification or the prosecution history, an intention to limit the claim scope of the Reference Patents to any narrower embodiments using words or expressions of manifest exclusion or restriction.16 Rather, the format illustrated in FIG. 2 of the specification is provided only as an "exemplary format"17 and should not be considered limiting. Given the absence of any format limitation that is expressly recited by the claims, incorporated by express definitions, or otherwise admitted by Applicant in the specification or prosecution history, Applicant respectfully submits that TriNKET format is not a limitation in the Reference Claims.
Despite the absence of format limitation in the claims, the Office refers to figures of the '733 Patents and asserts that "the claimed protein in '733 patent has F3-TriNKET or [F3']- TriNKET format shown in figure 2, while the instant claimed protein (claim 34) is defined to have F3'-TriNKET format shown in figure 1A. The Office further alleges that "the claimed protein/antibody in the '733 patent is a genus with two different species F3 and [F3'] in term of the format and one of the formats is claimed in the present application. The Office therefore construes the claim scope of the '733 Patents as being limited to the F3 and F3' formats. Specifically, the Office alleges that "the claimed protein in '733 patent is a [genus] of two species although the claims of the patent do not specifically define which tumor antigen binding domain is scFv or Fab (F3 and [F3'] format). The Office further alleges that "many of the antigen binding formats listed [in Figure 1 of] in Brinkmann & Kontermann (2017) mAbs, 9(2):182-212 ("Brinkmann") are outside the structural category, scFv of Fab, as claimed and discussed in" the '733 Patent.
Applicant submits that the Office has impermissibly read the features of FIG. 2 and its legend into the claims of the '733 Patent. As discussed in section I.B.2 above, "[t]hough understanding the claim language may be aided by explanations contained in the written description, it is important not to import into a claim limitations that are not part of the claim. Applicant submits that FIG. 2 merely provides an "exemplary format"of TriNKET to help a skilled person in the art to understand the invention, and this format should not be imported into the claims of the '733 Patent, which by itself is silent on TriNKET format. By confining the claim scope of the '733 Patent (and similarly, the other Reference Patents) to a genus of only two specific formats, the Office has construed the Reference Claims in a restrictive manner that is repeatedly warned against by the federal appellate courts. Accordingly, Applicant respectfully traverses the narrow claim construction adopted by the Office.
In response, applicant argues that the claims of ‘733 patent recite antibodies that have the structure beyond than the two formats described in the patent, which are not supported by the ‘733 Patent application as well as the other reference patent at the time of filing the applications. Applicant has not yet pointed out what kinds of the structures of the claimed bispecific antibodies could be in ‘733 Patent as well as the other reference patents other than the one arm being scFv and other arm being Fab with constant domain forming a heterodimer that binds to CD16 as described in the reference patents and present application. Therefore, as discussed in the previous Office action, the claimed bispecific antibodies in each of the reference patents indeed are genus containing a small number of species, and one of the them has the same structure and identical antigen binding domain sequence (F’3-format) as the instantly claimed antibody. Therefore, one skilled in the art would be motivated with high expectation of success to form an antibody comprising one arm being Fab to NKG2D and another arm being scFv to tumor antigen to arrive at current invention without unexpected result.
I.C. Differences between the instant claims and the reference claims
As discussed above, Applicant submits that none of Reference Claims specify the format of the NKG2D-binding site, the format of the additional antigen-binding site, or how these antigen-binding sites link to the dimer of antibody constant domains. Accordingly, the claims of the instant application, as amended herein, differ from the Reference Claims in at least the F3' format.
In response, the claimed antibody and reference patents have the identical antigen binding domain (VHCDR1-3 and VLCDR1-3 as well as VH and VL) in sequences and F’3- format, that have been addressed above.
II. Anticipation Analysis
As discussed in Section I.C above, Applicant submits that the Reference Claims do not recite the F3'-TriNKET format. Therefore, Applicant submits that the instant claims are novel over the Reference Claims.
In response, the argument has been addressed in details in the last Office action (III, application analysis, page 12), which is maintained for the reasons of record.
III. Obviousness Analysis
The MPEP states: "nonstatutory double patenting rejection, if not based on an anticipation rationale or an 'unjustified timewise extension' rationale, is 'analogous to [a failure to meet] the nonobviousness requirement of 35 U.S.C. 103' except that the patent disclosure principally underlying the double patenting rejection is not considered prior art."24 In the obviousness analysis: "the patent examiner must first set forth a prima facie case, supported by evidence, showing why the claims at issue would have been obvious in light of the prior art. Once the examiner sets out this prima facie case, the burden shifts to the patentee to provide evidence, in the prior art or beyond it, or argument sufficient to rebut the examiner's evidence."25"Rebuttal evidence may include evidence of 'secondary considerations,' such as ... evidence that the claimed invention yields unexpectedly improved properties or properties not present in the prior art."26
As discussed in more detail below, Applicant submits that the Office has failed to establish a prima facie case of obviousness. Furthermore, for the sake of argument only, Applicant's unexpected results are sufficient to overcome a prima facie case of obviousness, even if one could be made out.
III. A. Prima facie case of obviousness
In order to make a prima facie case of obviousness, the Office must demonstrate that differences between the claimed invention and the prior art are such that the claimed invention, as a whole, would have been obvious to a skilled person in the art before the effective filing date of the claimed invention.27 The MPEP states: "[e]xaminers must consider all claim limitations when determining patentability of an invention over the prior art
Applicant submits that the Reference Claims are completely silent about the requisite features of the F3'-TriNKET format. The Office alleges that "no matter what kind format, scFv or Fab in one or another arm, of the claimed protein/antibody is, the skilled artisan would clearly know and call them as antigen binding fragments that are the fragments from the same antibody as long as the full set of 6 CDRs are the same as original or full antibody. Applicant submits, however, that the Office did not cite any reference teaching the scFv or Fab elements of individual fragments of TriNKET, much less how they are linked to the antibody constant domains to form an F3' format as a whole. Rather, the Office relied upon the written description and figure 2 (but not claims) of the Reference Patents, which Applicant submits cannot be applied in the double patenting rejection. Accordingly, the Office has not identified teachings of all claim limitations in the Reference Claims or any eligible prior art to establish a prima facie case of obviousness.
The Office further alleges that "the skilled artisan is clear that the patentability of a novel antibody as a product is majorly and almost purely depending the novelty of 6 CDR amino acid sequences in combination, not a format or antibody fragment from the antibody, such as such as [sic] Fab, scFv, Fv, etc If a full antibody is new, novel and patentable, its antigen binding fragment, Fab, scFv, Fv, etc... comprising the same full CDRs are all novel and patentable without considering the format as claimed.
Applicant submits that the Office has mistakenly characterized the present invention as an antibody invention that relies solely upon CDR sequences for patentability. Rather, the present invention is directed to a TriNKET containing a sequence-specific NKG2D-binding site in a specific format which, as explained in Section III.B below, demonstrates a superior activity. Such a format feature can confer patentability to a TriNKET species, as claimed herein, over a CDR-sequence-specific TriNKET genus according to the Reference Claims. The Office has categorically excluded this format feature from consideration in the obviousness analysis, making a conclusory statement about antibody patenting that is not substantiated by either scientific facts or legal reasoning.
For at least the foregoing reasons, Applicant submits that the Office has failed to establish a prima facie case of obviousness in the double patenting analysis.
In response, applicant provides the same/similar arguments as set forth in the Remarks dated 5/2/2024 that have been addressed at pages 13-14 of the last Office action dated 5/30/2025, which is maintained for the reason of record.
III. B. Unexpected results
As discussed above, Applicant submits that the Office has not made out a prima facie case of obviousness. Applicant further submits that the claims, as amended herein, are nonobvious over the claims of the '733 Patent in view of the unexpectedly high activity of F3'-TriNKETs.
"It is well-settled that a narrow species can be non-obvious and patent eligible despite a patent on its genus. Secondary considerations, such as unexpected results, may be submitted to rebut an obviousness rejection. Evidence of unexpected results may be used to rebut a case of prima facie obviousness even if that evidence was obtained after the patent's filing or issue date.
Here, Applicant reiterates that the F3'-TriNKET format includes a combination of at least three technical features: (1) the antigen-binding site binding the target antigen is in an scFv, (2) the antigen-binding site binding NKG2D, having the CDR sequences recited in the instant claims, is in a Fab, and (3) both the scFv and the Fab are linked to the N-terminus of the dimer of antibody constant domains. These features, as a whole, confer an unexpected technical advantage to the F3'-TriNKET species over the TriNKET genus. To support this proposition, Applicant submitted a declaration of Gregory P. Chang on September 25, 2023 (the "Chang Declaration"), which demonstrates greater activity of proteins in the F3' format than corresponding proteins in the F3 format. "[B]ased on Mr. Chang's declaration the Office agrees that the antibody with F3'-TriNKETs format has advantages on tumor cell lysing over the antibody have F3-TriNKETs format.36 Accordingly, the skilled person would appreciate that the F3'-TriNKET format, having the unexpected technical advantage, would not have been obvious over the genus of TriNKET proteins.
For at least the foregoing reasons, Applicant submits that the present claims are patentably distinct from the claims of the Reference Patents. Accordingly, Applicant respectfully requests that the double patenting rejections to claims 34, 122, 127-131, 133-136, 138, and 140-145 over the Reference Claims be reconsidered and withdrawn. Claims 146-148 are canceled herein, rendering the rejections to these claims moot.
In response, again, applicant provides the same arguments including declaration of Gregory P. Chang on Sept 25, 2023 as set forth in the Remarks dated 5/2/2024 that have been addressed at pages 15-18 of the last Office action dated 5/30/2025, which are maintained for the reason of record.
For the reasons above, the non-statutory double patenting rejection for US Patents 11,884,733, 11,939,384, 12,129,300, and 12,264,200 are maintained and made again.
Conclusion
No claim is allowed.
Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/LEI YAO/Primary Examiner, Art Unit 1642