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 .
Election/Restrictions
Applicant’s election without traverse of Species 1: Claims 48-52 and 56-68 in the reply filed on 07/08/2026 is acknowledged. Further, claims 47-52, as indicated in the response, do read on the elected species.
Claims 53-55 and 80-90 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/08/2026.
Status of the Claims
Claims 53-55 and 80-90 are withdrawn in response to Applicant’s election. Claims 47-52 and 56-79 are pending and are examined herein.
Priority
This application, filed 04/25/2023, is a DIV of 16/539,756, filed 08/13/2019, which is a DIV of 14/402,574, filed 11/20/2014, which is a 371 of PCT/JP2013/064975, filed 05/30/2013, which claims benefit of JAPAN 2012-177311, filed 08/09/2012, and JAPAN 2012/123781, filed 05/30/2012. This priority is acknowledged and the claims examined herein are treated as having an effective filing date of 05/30/2012.
Information Disclosure Statement
The Information Disclosure Statements filed 05/31/2023, 06/05/2023, 07/26/2023, 11/02/2023, 01/30/2024, 05/06/2024, 06/14/2024, 07/08/2026, and 08/21/2026 are acknowledged and have been considered.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 47-52, 56, 59-69, and 72-79 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2006/0141456 A1, “METHODS AND COMPOSITIONS FOR MILIEU-DEPENDENT BINDING OF A TARGETED AGENT TO A TARGET” (published 06/29/2006, IDS dated 05/31/2023, referred to herein as Edwards).
Regarding claims 47-52, Edwards teaches methods relating to the selection of milieu-dependent targeted agents (MDTA) from a plurality of variants, i.e. a library (para. 0183, lines 1-2), that preferentially bind a target when it is present in one context, relative to when it is present in another context (see, for example, para. 0006, lines 1-5). Edwards teaches that the MDTA is an antibody (see, for example, para. 0057, lines 1-3). Edwards teaches a method of (a) assaying the binding of MDTA variants (see, for example, para. 0119, lines 1-11) under a first set of reaction conditions compared to a (b) second set of reaction conditions (see, for example, para. 0119, lines 1-11) for (c) determining improved binding under the first vs second condition (see, for example, para. 0119, lines 1-11). Edwards teaches (d) selecting the MDTA based on step (c) (see, for example, para. 0042, lines 1-4). Edwards teaches that the difference between the conditions is the presence (and by association, absence) or differences in concentration of a molecule, such as metals, salts, sugars, and/or amino acids, among others, that result in different binding affinity of the MDTA (see, for example, para. 0178, lines 1-9). Regarding the recitation of “wherein either the first concentration or the second concentration, but not both, can be zero”, the claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed (See MPEP 2111.04(I)). In this case, the limitation that a concentration can be zero, is not considered to require a concentration to be zero. Further, Edwards teaches the presence, and thus the absence, i.e. a concentration of zero, of a compound can be the difference between the first and second condition (see, for example, para. 0178, lines 1-9).
Regarding claims 56 and 69, Edwards teaches that the compound can be a nucleotide or an amino acid (para. 0178, lines 1-9).
Regarding claims 59 and 60, Edwards teaches that the difference in binding affinity of the MDTA between the first and second condition is at least 2-fold (para. 0113, lines 1-8). Edwards teaches that the difference in binding affinity in the two conditions is measured via calculating the dissociation constant, i.e. Kd (para. 0113, lines 8-15).
Regarding claims 61 and 72, Edwards teaches that the antigen is expressed on a cell membrane, i.e. the cell surface (para. 0270, lines 1-9).
Regarding claims 62 and 73, Edwards teaches producing an antigen-binding molecule comprising an antigen binding domain, i.e. the MDTA (para. 0192, lines 1-2).
Regarding claims 63 and 74, Edwards teaches neutralizing, i.e. inhibiting the activity of, the antigen target by binding to the MDTA (para. 0125, lines 1-13).
Regarding claims 64 and 75, Edwards teaches the MDTA has cytotoxic activity, i.e. a toxic activity (see, for example, para. 0125, lines 1-13 and para. 0129, lines 1-4).
Regarding claims 65 and 76, Edwards teaches that the antigen-binding domain comprises antibody heavy and light variable regions (see, for example, para. 0318, lines 1-5).
Regarding claims 66, 67, 77, and 78, Edwards teaches that the MDTA is an antibody (see, for example, para. 0057, lines 1-3) which comprises an Fc region (see, for example, para. 0350, lines 1-7).
Regarding claims 68 and 79, Edwards teaches a method of producing the MDTA comprising providing a cell containing DNA encoding the MDTA, expressing the DNA to produce the MDTA, and collecting the MDTA (see, for example, para. 0192, lines 1-10 and para. 0193, lines 1-11).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 57, 58, 70, and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Edwards in view of Lukashev et al. Cancer Metastasis Rev 2007; 26:273-79 (referred to herein as Lukashev, IDS dated 05/31/2023).
Edwards teaches methods and compositions for milieu-dependent binding of a targeted agent to a target. See entire document, e.g. Abstract. “Milieu-dependent targeted agents” (“MDTA”) are agents that preferentially bind to a microtarget (e.g, an epitope) when it is present in one context relative to when it is present in another context. E.g., [0006]. In one embodiment, the MDTA binds a microtarget on an unhealthy tissue but not on a healthy tissue. Id. Methods of identifying/selecting the MDTA are taught at, e.g., [0029]-[0056].
In one embodiment, the MDTA is an antibody or antibody fragment. E.g., [0057], Examples (MDTA is a single chain Fv).
Edwards teaches that the MDTA can bind a microtarget on a tumor cell or tissue. E.g., [0058], [0059], [0161]-[0180] and Examples (antibody binds the tumor antigen CEA). The milieu is the reaction conditions under with the MDTA binds its microtarget and includes the extracellular environment of a cell or the cellular context of a cell. E.g., [0060].
While Edwards exemplifies MDTA that bind in a pH (i.e., hydrogen ion)-dependent manner, Edwards makes clear that the difference between the first milieu that allows the MDTA to bind and the second milieu that does not may also be a difference in salt concentration, concentration of a solute such as lactic acid, or difference in concentration of other inorganic molecules. E.g., [0061], [0076], [0178], [0179]. Edwards notes that “[a]ny difference between a cancer cell or tumor and another cell or tissue, e.g., a healthy cell of tissue, can be exploited to make an MDTA that preferentially binds a microtarget in the cancer cell or tumor over the microtarget in the other cell or tissue." [0180].
Edwards does not teach that the concentration or presence/absence of any of the specifically claimed compounds in claims 57, 58 , 70, or 71, are the difference between the first and second milieu; i.e., "a compound that is present at a higher concentration in a target tissue than in a non-target tissue in a subject,".
Lukashev teaches that the tumor microenvironment is hypoxic and that levels of extracellular adenosine are increased. Lukashev, see entire document, e.g., Abstract. Lukashev teaches that this hypoxic environment is also present during tissue inflammation. E.g., Figure 1. In each situation, adenosine inhibits the activity of immune cells such as T cells. In the tumor environment, the T cell suppression helps the tumor escape T-cell-mediated destruction. E.g., Section 2, page 274.
In view of the teachings of Lukashev, the ordinary artisan before the effective filing date of the claimed invention would have found it prima facie obvious that adenosine would comprise a difference between tumor tissue and healthy tissue and that the adenosine concentration, like the hydrogen ion or salt concentration, could be used to select MDTA of Edwards that targeted an antigen on a tumor cell only in the presence of, or at a comparatively high concentration of, adenosine. Edwards provides methods of selecting MDTA that are antibodies to a tumor antigen that bind in a milieu-dependent manner. Adenosine would have necessarily been present when tumor tissue relative to healthy tissue was used in the MDTA selection process of Edwards.
The rationale to substitute one compound that was milieu-dependent for tumor tissue for another compound that was also milieu-dependent for a tumor cell is the recognition that the compounds were alternatives that would each be expected to yield MDTA/antibodies that could bind a target antigen only in the presence of that milieu-dependent molecule. Providing alternate MDTA, the binding of which was dependent on a second milieu-dependent compound, would have been desirable to provide alternate, and potentially complementary antibodies/MDTA that might be developed for therapeutic targeting of tumors. Substitution of one milieu-dependent molecule for another would, as taught by Edwards, have been expected to predictably yield alternate MDTA/antibodies and so is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143.
An artisan would have had a reasonable expectation of success in testing various concentrations or the presence/absence of adenosine for the selection of MDTAs with the methods taught by Edwards because, as taught by Edwards, “[a]ny difference between a cancer cell or tumor and another cell or tissue, e.g., a healthy cell of tissue, can be exploited to make an MDTA that preferentially binds a microtarget in the cancer cell or tumor over the microtarget in the other cell or tissue." (Edwards para. 0180). At the same time, Lukashev teaches that adenosine levels are increased in the tumor microenvironment and results in the inhibition of anti-tumor T-cells, which has dramatic phenotypic consequences in the tumor environment (Abstract, see for example, p. 274, col. 1, para. 1, lines 1-6 and col. 2, paras. 1 and 2). An artisan would recognize, based on these teachings, that varying levels of adenosine would result in phenotypic differences within tumor microenvironments and would be useful for identifying MDTAs with utility for binding targets within that environment.
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 47-52, 56, 59-69, and 72-79 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 11 and 12 of U.S. Patent No. 11,912,989 B2 (referred to herein as ‘989 in view of Edwards.
Regarding instant claims 47 and 50, ‘989 claims a method of screening for an antigen-binding domain whose activity varies depending on the concentration of a compound comprising contacting a plurality of antigen-binding domains with an antigen in the presence of a first and second concentration of a compound, determining the binding affinity and selecting the antigen binding domain based on the binding affinity (‘989 claim 11).
Regarding instant claim 48 and 51, ‘989 claims that the first concentration is higher than the second concentration and the binding is higher in the first concentration than the second concentration (‘989 claim 11, lines 9-17).
Regarding instant claims 65 and 66, ‘989 claims the antigen binding molecule is an antibody comprising heavy and light chains (‘989 claim 12).
However, ‘989 does not claim that the compound is a natural chemical substance that is not a biopolymer and is not hydrogen ion (instant claim 47). ‘989 does not claim the embodiments claimed in the dependent claims 48, 52, 56, 59-69, and 72-79 of the instant application.
The teaching of Edwards, as described above in the rejection under 35 U.S.C. 102, are incorporated herein.
Regarding instant independents claim 47 and 50, Edwards teaches that a compound used for varying the binding of a concentration-dependent antigen binding domain are metals, salts, sugars, and/or amino acids, among others (see, for example, para. 0178, lines 1-9).
Regarding instant dependent claims 48, 52, 56, 59-69, and 72-79, see the detailed teachings of Edwards above in the rejection under 35 U.S.C. 102.
It would have been prima facie obvious to one of skill in the art before the effective filing date of the claimed invention to combine the claimed method of ‘989 with the specific embodiments taught by Edwards. Doing so is considered to be Combining Prior Art Elements According to Known Methods To Yield Predictable Results (See MPEP 2143(I)(A)). Edwards is considered to teach the specific embodiments, as claimed in the instant invention, of the generic method claimed by ‘989. An artisan would have readily used the detailed method taught by Edwards to predictably accomplish the generically claimed method of ‘989.
Claims 57, 58, 70, and 71 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 11 of U.S. Patent No. 11,912,989 B2 (referred to herein as ‘989) in view of Edwards and Lukashev.
Regarding claims 57, 58, 70, and 71, ‘989 in view of Edwards teaches the use of a compound to vary the concentration-dependent binding of an antigen-binding domain (‘989 claim 11).
‘989 in view of Edwards does not teach that the concentration or presence/absence of any of the specifically claimed compounds in claims 57, 58 , 70, or 71, are the difference between the first and second milieu; i.e., "a compound that is present at a higher concentration in a target tissue than in a non-target tissue in a subject,".
The teaching of Lukashev, as described above in the rejection under 35 U.S.C. 103 regarding claims 57, 58, 70, and 71, are incorporated herein.
Lukashev teaches that the tumor microenvironment is hypoxic and that levels of extracellular adenosine are increased. Lukashev, see entire document, e.g., Abstract. Lukashev teaches that this hypoxic environment is also present during tissue inflammation. E.g., Figure 1. In each situation, adenosine inhibits the activity of immune cells such as T cells. In the tumor environment, the T cell suppression helps the tumor escape T-cell-mediated destruction. E.g., Section 2, page 274.
In view of the teachings of Lukashev, the ordinary artisan before the effective filing date of the claimed invention would have found it prima facie obvious that adenosine would comprise a difference between tumor tissue and healthy tissue and that the adenosine concentration, like the hydrogen ion or salt concentration, could be used to select antigen-binding domain of ‘989 in view of Edwards that targeted an antigen on a tumor cell only in the presence of, or at a comparatively high concentration of, adenosine. Edwards provides methods of selecting MDTA that are antibodies to a tumor antigen that bind in a milieu-dependent manner. Adenosine would have necessarily been present when tumor tissue relative to healthy tissue was used in the MDTA selection process of Edwards.
The rationale to substitute one compound that was milieu-dependent for tumor tissue for another compound that was also milieu-dependent for a tumor cell is the recognition that the compounds were alternatives that would each be expected to yield MDTA/antibodies that could bind a target antigen only in the presence of that milieu-dependent molecule. Providing alternate MDTA, the binding of which was dependent on a second milieu-dependent compound, would have been desirable to provide alternate, and potentially complementary antibodies/MDTA that might be developed for therapeutic targeting of tumors. Substitution of one milieu-dependent molecule for another would, as taught by Edwards, have been expected to predictably yield alternate MDTA/antibodies and so is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143.
An artisan would have had a reasonable expectation of success in testing various concentrations or the presence/absence of adenosine for the selection of MDTAs with the methods taught by Edwards because, as taught by Edwards, “[a]ny difference between a cancer cell or tumor and another cell or tissue, e.g., a healthy cell of tissue, can be exploited to make an MDTA that preferentially binds a microtarget in the cancer cell or tumor over the microtarget in the other cell or tissue." (Edwards para. 0180). At the same time, Lukashev teaches that adenosine levels are increased in the tumor microenvironment and results in the inhibition of anti-tumor T-cells, which has dramatic phenotypic consequences in the tumor environment (Abstract, see for example, p. 274, col. 1, para. 1, lines 1-6 and col. 2, paras. 1 and 2). An artisan would recognize, based on these teachings, that varying levels of adenosine would result in phenotypic differences within tumor microenvironments and would be useful for identifying MDTAs with utility for binding targets within that environment.
Conclusion
No claims are allowable.
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/C.E./Examiner, Art Unit 1677
/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
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