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 .
1. The Amendment filed November 20, 2025 in response to the Office Action of June 20, 2025, is acknowledged and has been entered. Claims 6, 12-14, 62-75 are pending. Claim 6 is amended. Claims 63 and 72 remain withdrawn. Claims 6, 12-14, 62, 64-71, and 73-75 are currently being examined as drawn to the antibody class comprising:
Heavy chain variable region CDRs 1-3:
SEQ ID NO:2 (Formula II) YSI[ST]SG[HY][HY]W[SAD]WI
SEQ ID NO:35 LARIDWDDDKYYSTSLKSRL
SEQ ID NO:7 (Formula VII) AR[GRS][AIY][DVY][YEA]FD[IY]
Light chain variable region CDRs 1-3:
SEQ ID NO:12 (Formula XII) RASQ[ST]V[FRS][GS]R[FY]LA
SEQ ID NO:14 [AD]AS[NST][LR][ASQ][ST]G[IV]
SEQ ID NO:15 (Formula XV) YC[EQV][HQ][AGHRS][DLSY][EGPQS][LTVW]P[FLPWY]T
Rejection Maintained
Improper Markush Grouping
2. Claims 6, 12-14, 62, 64-71, and 73-75 remain rejected on the basis that claim 6 contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of anti-CTLA-4 antibodies is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Although the Markush grouping encompass antibodies having a common function of binding to CTLA-4, the antibodies do not have a single structural similarity. The Markush grouping encompasses different “classes” of antibodies having structurally distinct formula sequences for HVR-H1, -H2, -H3, -L1, -L2, and -L3.
Examiner provides a comparison of the structurally unrelated antibodies claimed in the Markush group compared to the species elected and examined in order to demonstrate that they do not have a single structural similarity in the CDRs critical to their CTLA-4-binding function. Below is an exemplary comparison of HVR-HL1, -H2, -H3 structures in claim 6 for the Markush group of heavy chain variable region CDRs (examined species are in bold font):
HVR-H1 (CDR1):
SEQ ID NO:2 (Formula II) YSI[ST]SG[HY][HY]W[SAD]W
SEQ ID NO:1 (Formula I) [FY]TFS[DG]Y[AGW]IHWV
SEQ ID NO:3 (Formula III) FSLSTGGVAV[GS]WI
HVR-H2 (CDR2):
SEQ ID NO:35 LARIDWDDDKYYSTSLKSRL
SEQ ID NO:4 (Formula IV) IG[DE]I[SY]HSGSTYYS[PQ]SLKSRV
SEQ ID NO:5 (Formula V) IG[IW]ISPS[SY]G[GS]T[ST]YAQKFQGRV
SEQ ID NO:6 (Formula VI) VS[AGS]ISG[SY]G[GS][ST]TYYADSVKGRF
HVR-H3 (CDR3):
SEQ ID NO:7 (Formula VII) AR[GRS][AI][DVY][AEY]FD[IY]
SEQ ID NO:8 (Formula VIII) AR[DL]G[FY]GYFD[VY]
SEQ ID NO:9 (Formula IX) AR[LR][IP][AY][ST]A[TY][AY]FDY
SEQ ID NO:10 (Formula X) ARD[IV][AH][PS]GSSGYY[DY]GFD[FV]
As exemplified above, the Markush groups of antibodies do not share heavy chain variable region CDR sequence structure with the elected and examined species of antibody, therefore the members of the claimed Markush group do not share a single structural similarity. Similar reasoning applies to the light chain variable region CDRs, wherein the Markush groups of antibodies do not share light chain variable region CDR sequence structure with the elected/rejoined and examined class of antibody.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Response to Arguments
3. Applicants argue that mere structural differences amongst claimed sequences are inadequate in establishing an improper Markush grouping. Applicants argue that the Patent and Trademark Appeal Board (PTAB) has taken an expansive view of what constitutes structural similarity that can link members of a Markush group. Applicants argue that broadest definition was found in Ex parte Buyyarapu (Appeal 2018-006665, US Ser. No. 14/212,469). In Ex parte Buyyarapu, an Examiner issued an improper Markush group rejection of a claim reciting "at least one marker that is linked to the RN resistance trait, the marker being selected from the group consisting of SEQ ID NOs: 58-62". The PTAB expressly stated that mere sequence differences of genes was not sufficient to render a group improper:
To the extent Examiner applied a bright-line rule that focused solely on the sequence differences without consideration of other structural similarities, that approach is incorrect. See Harnis[c]h, 631 F.2d at 722 ("[I]n determining the propriety of a Markush grouping the compounds must be considered as wholes and not broken down into elements or other components."); see also MPEP § 706.03 (y)(IV).
The PTAB performed its own analysis and found a "structural similarity" between the genes based upon "their specific physical proximity to each other and overall location within [the] cotton genome," and a "common use" as markers of plant resistance to a particular pest. Thus, the genes happening to be in a similar location in the plant genome was sufficient for "structural similarity." Most notably, there was no actual physical relationship between the genes. In Ex parte Narva (Appeal 2018-006168, Application No. 14/577,811), the PTAB reversed an Examiner's improper Markush rejection of claims reciting several inhibitory double- stranded RNAs. The PTAB agreed with the Applicant's position that "a single structural similarity does not require nucleotide sequence level granularity" and concluded that "[w]e agree with Appellants that the claimed Markush group is not improper." Applicants argue that in addressing structural similarity, the PTAB noted that the "nucleic acid sequences recited in the rejected claims belong to the same recognized chemical class of polyribonucleotides that are hybridized in dsRNA molecules and encode ROP proteins."
Applicants argue that in the present case, there is a very clear relationship between the claimed HVRs. The HVR regions recited in the claims are present at precise locations within the variable heavy and variable light chains of the anti-CTLA4 antibody and interact with an epitope of their target antigen in a similar manner. Therefore, for similar reasons articulated in the decisions above, the groupings of HVRs recited in the claims is not improper.
4. The arguments have been carefully considered but are not persuasive. As stated and demonstrated in the rejection of record, claim 6 lists several different classes of CTLA-4 antibodies that do not overlap in sequence structure and do not have any shared core sequence homology, therefore the members of the claimed Markush group do not share a single structural similarity. Applicants made no arguments against this.
Instead, Applicants have argued that the CTLA-4 antibodies have a common use and pointed to an appeal board decision Ex parte Buyyarapu (Appeal 2018-006665, US Ser. No. 14/212,469) to support their arguments. The arguments are not persuasive because the fact patterns in Ex parte Buyyarapu are not commensurate in scope with the instant claims and the decision is not applicable here.
In Ex parte Buyyarapu, the claim at issue was a method claim, where five sequence markers (SEQ ID NOs:58-62) have a shared use in producing a cotton plant comprising reniform nematode (RN) resistance:
A method for producing a cotton plant comprising reniform nematode (RN) resistance, the method comprising: crossing a first parental cotton plant comprising the trait of RN resistance with a second parental cotton plant that is sensitive to RN infection as compared to the first parental cotton plant, to produce progeny cotton plants, wherein the first parental cotton plant comprises at least one marker that is linked to the RN resistance trait, the marker being selected from the group consisting of SEQ ID NOs:58- 62, and wherein the second parental cotton plant does not comprise the marker that is linked to the RN resistance trait; isolating genomic DNA from the progeny cotton plants; screening the genomic DNA of the progeny cotton plants for the presence of the marker that is linked to the RN resistance trait; and selecting a progeny cotton plant having genomic DNA comprising the marker that is linked to the RN resistance trait, thereby producing a cotton plant comprising RN resistance.
In the instant case, unlike in Ex parte Buyyarapu, there is no claimed method and no shared claimed use for the anti-CTLA-4 antibodies. In the instant case, unlike in Ex parte Buyyarapu, there is no "structural similarity" between the anti-CTLA-4 antibody sequences based upon "their specific physical proximity to each other and overall location within a genome”. Therefore, the fact pattern applied to the decision in Ex parte Buyyarapu is not analogous to the instant claims.
Applicant’s arguments that the HVR (CDR) regions recited in the claims are present at precise locations within the variable heavy and variable light chains of the anti-CTLA4 antibody and interact with an epitope of their target antigen in a similar manner is not persuasive. The position of HVR (CDR) regions in an antibody structure is not unique to CTLA-4 antibodies or to the classes of antibodies claimed. The standard IgG antibody structure comprises three CDRs (HVRs) on the heavy chains and three CDRs (HVRs) on the light chains regardless of what antigen the antibody recognizes and binds. All IgG antibodies have this structure with the heavy chain and light chain CDRs (HVRs) located in the same position regardless of what different antigens are bound and recognized (see Figure below):
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Contrary to arguments, the standard location of CDRs (or HVRs) on an IgG antibody is not the determining factor for antigen binding or even epitope binding, it is the CDR (HVR) sequences that are critical to determining CTLA-4 antigen binding, as well as epitope binding. Again, claim 6 lists several different classes of CTLA-4 antibodies that do not overlap in sequence structure and do not have any shared core sequence homology, therefore the members of the claimed Markush group do not share a single structural similarity and the Markush grouping is improper.
Examiner disagrees that a shared sequence homology between antibody CDR (HVR) sequences is not required for proper Markush grouping of antibodies. According to Applicant’s logic and arguments, every IgG anti-CTLA-4 antibody in the universe, regardless of CDR (HVR) sequence homology or lack thereof, would be properly encompassed as part of the same claimed Markush grouping because they all function to bind the same antigen. Examiner maintains that the shared generalized function of binding CTLA-4 antibody is not sufficient to properly place structurally distinct classes of antibodies into one Markush group. MPEP 2117 states: “A Markush grouping is proper if the members of a group share a single structural similarity and a common use.” Examiner maintains that instant claim 6 lists several different classes of CTLA-4 antibodies that do not overlap in sequence structure and do not have any shared core sequence homology, therefore, the members of the claimed Markush group do not share a single structural similarity and the Markush grouping is improper. It is also noted that the instant claims are not directed to a method, therefore do not claim a common use.
MPEP 2117 states that in In re Harnisch, 631 F.2d 716, 206 USPQ 300 (CCPA 1980), coumarin compounds having different functional groups were claimed, where the Markush grouping was deemed proper because all of the compounds shared "a single structural similarity" which is the coumarin core. In the instant case, the anti-CTLA-4 antibody classes claimed do NOT share any CDR (HVR) structural similarity and do NOT share a common sequence core. The classes of CTLA-4 antibodies claimed do not share a substantial single structural similarity. Therefore, the Markush grouping of the different classes of anti-CTLA-4 antibodies is improper.
5. All other objections recited in the Office Action mailed June 20, 2025 are hereby withdrawn in view of amendments. The nonstatutory double patenting rejections over U.S. Patent No. 11,692,036 and U.S. Patent No. 11,359,016 are withdrawn in view of terminal disclaimer filed November 20, 2025.
6. Conclusion: No claim is allowed.
Conclusion
7. 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.
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Laura B Goddard/Primary Examiner, Art Unit 1642