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 .
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.
Status of Claims
Claims 21-24 are pending and under examination. Claims 1-20 are canceled.
Maintained Rejections
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 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Belosludtsev et al. (PGPUB US2019/0233447A1, published 08/01/2019, of record) in view of Gerg et al. (US2019/0324025A1, published 10/24/2019).
With respect to claims 21 and 23-24, Belosludtsev teaches a caged hapten and caged hapten-antibody conjugates are useful for enabling the detection of targets located proximally to each other in a sample (see abstract). Belosludtsev teaches analyzing a sample to determine whether a first target is proximal to a second target through a method of using caged hapten (see para. [0008]). In particular, Belosludtsev teaches that caged haptens disclosed herein have been designed with an enzyme cleavable cage such that the respective hapten, i.e., the uncaged or unmasked hapten, is released by enzymatic treatment to regenerate the native hapten and thus, in the presence of an appropriate enzyme, the caged hapten is unmasked and an anti-hapten antibody is free to bind to it (see, for example, Fig. 2 and para. [0165]). Belosludtsev teaches that the caged haptens having a general Formula I (see paras. [0165]-[0171] and reproduced below):
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Additionally, wherein X has a structure of Formulas (IIIA-D) wherein d and e are integers each independently ranging from 1 to 24; Q is an amine group (see paras. [0238][0239]). Belosludtsev further teaches a spacer having the chemical structure (see pg. 20, before para. [0255] or reproduced below).
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Belosludtsev teaches that a specific example of the hapten may be digoxigenin (i.e., DIG, see paras. [0173]-[0174]). As evidenced by Gerg et al., digoxigenin is depicted as (see Fig. 2J):
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. Thus, Belosludtsev’s digoxigenin teaches the claimed hapten structure without the spacer group and the phosphate moiety. Belosludtsev teaches a method of forming a target-caged hapten-antibody conjugate complex and performing a decaging step such that an unmasking enzyme reacts (i.e., hydrolysis) an enzyme substrate portion of the first target-caged hapten antibody conjugate complex (see paras. [0012] and [0145]; and Fig. 12). Belosludtsev teaches the enzyme substrate is a phosphate group portion (see para. [0028]). Belosludtsev also teaches an example of a caged hapten with PO3H2 directly attached (i.e., without a leaving group) to the hapten (see structure of para. [0249], pg. 17, right col., 3rd structure down). Belosludtsev teaches linking a maleimide reactive group via a spacer (see paras. [0251]-[0253]). Belosludtsev teaches the use of alkaline phosphatase (AP) as an enzyme that removes (by hydrolysis) and transfers phosphate group organic esters by breaking the phosphate-oxygen bond (see para. [0145]). Belosludtsev teaches that it is believed that proximity assay is more general than merely measuring protein-protein interactions and in this case, if one antibody is directed against an epitope on a protein (e.g. HER2), and a second antibody is directed against all phosphor-tyrosines, then the proximity signal would represent all the phosphorylated HER2 proteins. Therefore, this type of assay is more binary (yes/no) than pairs of proteins that interact with each other (see para. [0321]; i.e., protein-protein interaction).
Even though Belosludtsev teaches that a specific example of a hapten is digoxigenin and maleimide spacer group, the reference does not exemplify the digoxigenin hapten attaching to a phosphate group (claim 23) and with the claimed maleimide spacer (claims 21-22 and 24).
Gerg teaches a hapten wherein the hapten is a digoxigenin compound useful to capture desired antibodies (see abstract and paras. [0080] and [0146]). Fig. 2J shows:
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Gerg teaches the linker has a backbone of a straight C1-C20 chain (see para. [0132]). Gerg further teaches a wide range of bifunctional hydrocarbon crosslinkers (see para. [0133]-[0140]). Gerg also teaches NHS-maleimide crosslinkers (see para. [0134]). Gerg also teaches facilitating conjugation to reactive moieties on a molecule of interest (see para. [0006]).
With respect to the digoxigenin hapten having a phosphate group, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated a phosphate group at the hydroxyl position of the digoxigenin hapten to produce a caged hapten for the proximity assay of protein-protein interactions (i.e., dimerizations) because Belosludtsev specifically discloses digoxigenin as the alternative hapten and phosphate group is the caging moiety for the hapten. Thus, it would have been obvious to the person to have incorporated the phosphate group into digoxigenin because Belosludtsev teaches the detection of protein-protein interaction relies on the hydrolysis of the phosphate group when the proteins are proximity of each other.
Additionally, it would have been obvious to have incorporated the phosphate group at the C-12 hydroxyl position of digoxigenin because Belosludtsev teaches that the hydroxyl group on the hapten is a functional group for covalent binding to the caging group (see Fig. 1A-B) and phosphate is a caging group that is covalently bound at the hydroxyl position of the hapten (pg. 17, right col., 3rd structure 3). Thus, it would have been obvious to have attached the phosphate group at the C-12 hydroxyl position of digoxigenin because digoxigenin only has three (3) hydroxyl sites that is conserved for covalent binding without adding additional functional groups nor forfeiting the integrity of the digoxigenin structure for antibody binding after the hydrolysis of the phosphate group (see Fig. 2).
With respect to the claimed maleimide spacer, it would have been obvious to have modified the maleimide spacer as taught by Belosludtsev with additional hydrocarbons as taught by Gerg because Gerg teaches that the hydrocarbon linker facilitates conjugation to reactive moieties while enabling antibody affinity interaction. Thus, it would have been obvious to have added additional hydrocarbon groups to Belosludtsev’s bifunctional linker to facilitate or adjust the proximity to the assay with the digoxigenin hapten.
Furthermore, Belosludtsev does recognize modifying the hydrocarbon spacer between 1 to 24 carbons. Since Belosludtsev teaches that the maleimide spacer has a range of carbon atoms between 1 and 24 carbons and Gerg teaches that hydrocarbon spacer for digoxigenin facilitates conjugation to reactive moieties, a prima facie case of obviousness exists. See MPEP 2144.05.
The person would reasonably expected success in forming the claimed compound because it has been well understood by Belosludtsev and Gerg to adjust or modify spacers for binding affinity between hapten and antibodies such as digoxigenin.
With respect to claim 22, as stated above, Belosludtsev teaches digoxigenin as the hapten, does not explicitly teach the claimed stereochemistry of digoxigenin. Gerg teaches the stereochemistry of digoxigenin (see 2J or claim 2). Thus, it would have been obvious to the person to have produced the claimed stereochemistry as Gerg teaches that digoxigenin is produced through stereochemistry forms.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claim 21 is provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claim 20 of copending Application No. 17/149911 (‘911) ((PGPUB US20210221833A1, published 07/22/2021, IDS submitted on 07/10/2023). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
The copending Application ‘911 recites a caged hapten having the structure:
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Although the copending ‘911 application recites the phrase “caged hapten” and the instant claim recites a compound, the recitations do not establish any structural differences in scope, as the caged hapten is a compound having the claimed structure.
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 22-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 20 of copending Application No. 17/149911 (‘911) (PGPUB US20210221833A1, published 07/22/2021, IDS submitted on 07/10/2023) in view of Gerg et al. (US2019/0324025A1, published 10/24/2019).
The copending claim 20 of Application ‘911 recites a caged hapten having the structure:
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However, the copending Application ‘911 does not explicitly recite the claimed stereochemistry of instant claim 22 nor does it recite only the digoxigenin structure of instant claim 23. Gerg has been discussed in the above rejection. Thus, it would have been obvious to the person at the time of filing to have modified the caged hapten of the copending Application ‘911 with the stereochemistry of Gerg because Gerg recognizes that digoxigenin is produced in stereochemistry form. Additionally, it would have been obvious to have produced the caged hapten of the copending Application ‘911 prior to adding spacers because Gerg teaches spacers are added on chemical structures to digoxigenin compound.
This is a provisional nonstatutory double patenting rejection.
Claim 24 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 20 of copending Application No. 17/149911 (‘911) (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because copending Application ‘911 recites a species of the instant claimed Formula (IIF). Thus, the copending claim 20 would read on the claimed chemical structure of instant claim 24.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 08/07/2025 have been fully considered but they are not persuasive.
35 U.S.C.103 rejection:
Applicant argues on page 1 of the Remarks that Beloshudtsev is directed to novel “caged” haptens which is to shield a hapten and the skilled artisan would thus appreciate that Belosludtsev discloses modifying haptens to prevent immunoreactivity. Gerg teaches the opposite of Belosludtsev, namely increasing the binding affinity of a monoclonal antibody to a biotinylated molecule. According to Gerg, the purpose of the biotinylated compounds having Formula I is to enhance the specificity and binding affinity in immunoassays. Thereby improving the detection and measurement of analytes in various samples. On pages 3-4, Applicant argues that importantly, Gerg discloses that a monoclonal antibody is only able to bind to the biotin moiety of a biotinylated compound when biotin is conjugated via one of the ring positions. Thus, it is clear that Gerg teaches increasing the binding affinity of monoclonal antibodies towards biotinylated molecules and this is the antithesis of the goal of Belosludtsev which teaches the inclusion of a group to prevent a hapten from being recognized by an antibody. Gerg provides no disclosure or suggestion that any other hapten may be shielded; or where moieties may be coupled to a hapten to prevent antibody recognition.
With respect to claim 23 (no linking group), Applicant argues on page 5, paras. 2-3, of the Remarks that none of the cited references teach any hapten including a directly attached phosphate group, where the hapten includes no further substitutions. The haptens of Belosludtsev require both a caging group and the groups [X] and [Y], both of which are absent in the compound of claim 23. Gerg does not cure the deficiency.
The arguments are not found persuasive for the following reasons. Even though Belosludtsev teaches caging digoxigenin to be shielded from the initial reaction via phosphate group, the reference teaches the phosphate is a leaving group that is removed so antibody affinity is used for detection (see Fig. 2). Meanwhile, Gerg does teach digoxigenin linking to biotin to produce a biotinylated digoxigenin structure with optimization to the orientation of biotin; however, the important aspect of Gerg is the ability for digoxigenin at a specific position to conjugate to another chemical structure (biotin) that retains digoxigenin’s functionality and integrity via a linker. The artisan would appreciate through Gerg that digoxigenin at a specific position can be extended via a linker to further conjugate. Note that Belosludtsev teaches a similar linker as claimed for conjugation (see above). As recognized in the art (e.g., Belosludtsev and Gerg) that chemical modification to digoxigenin would hinder the intended antibody to detect digoxigenin. Therefore, Gerg teaches digoxigenin’s conjugation at a specific position without hindering the ability for antibody detection because Belosludtsev requires the hapten (digoxigenin) to be conjugated for antibody detection.
With respect to claim 23, the argument is not found persuasive. Although Belosludtsev and Gerg do teach modification to digoxigenin with spacers and linkers, Belosludtsev teaches that the native hapten is conjugated to the phosphate cage group prior to further modify with spacers and linking groups (e.g., Fig. 1c). Thus, the artisan would arrive at the caged digoxigenin prior to any further modification to incorporate a linking group.
Statutory type (35 U.S.C. 101) and nonstatutory double patenting rejections:
Applicant argues on page 5, paras. 3-4, of the Remarks that these double patenting rejections be held in abeyance. The arguments are not found persuasive for the following reasons.
With respect to the statutory type double patenting rejection over instant claim 21, the rejection is maintained until the claims are amended or canceled in either application. Note that a terminal disclaimer will not overcome a statutory type rejection.
With respect to the nonstatutory double patenting rejections over claims 22-24, the rejection is maintained until Applicant files a terminal disclaimer.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NAM P NGUYEN whose telephone number is (571)270-0287. The examiner can normally be reached Monday-Friday (8-4).
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/N.P.N/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678