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
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-3, 6-8, 10, 13, 36, 39, and 41-43 have an effective filing date of 06JUL2018.
Election/Restriction
In the response filed on 12/18/2024, Applicant elected:
Group I, claims 1-3, 5, 10, and 13
Species
A subtype of anti-PD-L1
The flexible amino acid sequence includes GGSGGS
The site of inserting the flexible amino acid sequence of GG (138/139)
Status of Claims
Claims 1-3, 6-8, 10, 13, 36, 39, and 41-43 are currently pending and presented for examination on the merits.
Claims 6-8, 36, and 39 are withdrawn from further consideration by Examiner under 37 CFR 1.142(b) as being drawn to a non-elected invention.
Claims 1, 10, and 13 are amended.
Claims 41-43 are new.
Rejections Withdrawn
The rejection filed under 35 U.S.C. 112(b) are withdrawn in view of Applicant’s amendments to claims.
The rejection of claim 13 filed under 35 U.S.C. 103 is withdrawn in view of Applicant’s arguments.
The rejection filed under Double Patenting (‘778) is withdrawn.
Rejections Maintained
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.
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 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 1-3, and 10, and 41-43 are rejected under 35 U.S.C. 103 as being unpatentable over Thompson et al (US 20080227958 A1, IDS 12/18/2024), Corey et al (US 20180147257 A1), Collier et al (WO 2017035508 A1), and further in view of Glaser et al (WO2018075692 A2).
Thompson et al teaches a method of modifying a binding proteins affinity and/or specificity for a cognate receptor [Abstract]. Thompson et al further teaches modifying an immunoglobulin hinge region [0023]. Thompson et al further teaches binding proteins include modified antibodies and antibody fragments [Abstract]. Thompson et al further teaches binding proteins are capable of antibody-dependent cellular cytotoxicity (ADCC) [0133]. Thompson et al further teaches addition of certain amino acids conferring flexibility [0009]. Thompson et al further teaches modifying the constant region of the antibody [Abstract]. Thompson et al further teaches conformational changes modified by the flexible region may affect the effector functions of the Fc portion of the antibody [0009]. Thompson et al further teaches utilizing an IgG1 antibody [0128].
Thompson et al does not specifically teach an ADCC-inducing antibody comprising PD-L1. However, this deficiency is made up in the teachings of Corey et al.
Corey et al teaches an ADCC-inducing antibody [0010]. Corey et al further teaches a polypeptide with a fusion partner [0008]. Corey et al further teaches fusion protein is partner with PD-L1 [0014].
Thompson et al does not specifically teach the flexible amino acid sequence of GGSGGS. However, this deficiency is made up in the teachings of Collier et al.
Collier et al teaches a fusion protein with a modified linker [0355]. Collier et al further teaches the linker is a flexible linker [0355]. Collier et al further teaches the linker comprising the amino acids GGSGGS [0355]. Collier et al further teaches linker may be required for negative steric effects [0243].
Thompson et al does not specifically teach modifying the antibody at position 138. However, this deficiency is made up in the teachings of Glaser et al.
Glaser et al teach a modified antibody [0161]. Glaser et al further teaches modifying the constant heavy chain at position 138 [0161].
One of ordinary skill, before the effective filing date, would have been motivated to combine Thompson’s method of modifying a ADCC binding protein comprising a linker region to modifying the effector functions, with Corey’s ADCC-inducing antibody comprising a fusion protein partner of anti-PD-L1, with Collier’s fusion protein comprising a linker with amino acid sequence of GGSGGS, with Glaser’s modification of the constant heavy region 138. The idea of combining them flows logically from their having been individually taught in the prior art (MPEP 2144.06). Combining prior art elements according to known methods to yield predictable results is an exemplary rationale for a prima facie case of obviousness. MPEP2143. It would have been prima facie obvious to combine Thompson, Corey, Collier, and Glaser’s teachings for a method of reducing Fc-mediated activities comprising inserting a flexible amino acid sequence in a constant region of a heavy chain, because Thompson teaches that changes modified by the flexible region may affect the effector functions of the Fc portion of the antibody.
Applicant’s Argument’s:
The Examiner's Combination Lacks Motivation
Thompson focuses on modulating Fc receptor binding affinities through mutations in the Fc region and/or glycosylation sites.
Thompson Teaches Away from the Claimed Invention
Thompson's Example 1 (0188) specifically uses amino acids with "either long or bulky side chains" to modify Fc receptor binding affinity. This is in direct contrast to the present invention, which emphasizes the use of amino acids with smaller side chains (glycine and serine) to provide flexibility.
Collier's Flexible Linkers Serve a Different Purpose
The use of flexible linkers to connect protein fragments is fundamentally different from their use to interrupt mechanical stress transmission in a constant region.
Corey Teaches Contrary Objectives
Corey discloses ADCC-inducing antibodies (0010), which is directly opposite to the objective of the present invention-reducing or eliminating ADCC/CDC activity. A person of ordinary skill in the art seeking to reduce ADCC/CDC would not look to Corey, which focuses on enhancing ADCC activity.
Glaser Does Not Provide Motivation
Glaser merely discloses modifications at position 138 of the heavy chain without teaching the specific purpose or effect of such modification, and certainly without any teaching regarding reducing ADCC/CDC activity through flexible amino acid sequence insertion.
The Cited Art Does Not Teach or Suggest the Claimed Insertion Configuration or Its Reported Effect
The references cited do not teach or suggest the above-recited insertion configuration in the IgG1 heavy-chain constant region for the purpose of reducing or eliminating ADCC/CDC activity, nor do they provide a reasoned expectation that such an insertion would achieve the recited functional outcome.
Examiner’s Response:
MPEP 2143.01 (I)states that
The disclosure of desirable alternatives does not necessarily negate a suggestion for modifying the prior art to arrive at the claimed invention. In In re Fulton, 391 F.3d 1195, 73 USPQ2d 1141 (Fed. Cir. 2004), the claims of a utility patent application were directed to a shoe sole with increased traction having hexagonal projections in a "facing orientation." 391 F.3d at 1196-97, 73 USPQ2d at 1142. The Board combined a design patent having hexagonal projections in a facing orientation with a utility patent having other limitations of the independent claim. 391 F.3d at 1199, 73 USPQ2d at 1144. Applicant argued that the combination was improper because (1) the prior art did not suggest having the hexagonal projections in a facing (as opposed to a "pointing") orientation was the "most desirable" configuration for the projections, and (2) the prior art "taught away" by showing desirability of the "pointing orientation." 391 F.3d at 1200-01, 73 USPQ2d at 1145-46. The court stated that "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." Id. In affirming the Board’s obviousness rejection, the court held that the prior art as a whole suggested the desirability of the combination of shoe sole limitations claimed, thus providing a motivation to combine, which need not be supported by a finding that the prior art suggested that the combination claimed by the applicant was the preferred, or most desirable combination over the other alternatives. Id. See also In re Urbanski, 809 F.3d 1237, 1244, 117 USPQ2d 1499, 1504 (Fed. Cir. 2016).
The teachings of Thomspon et al, Collier et al, Corey et al, and Glaser et al do not criticize, discredit, or otherwise discourage the use of a linker and reducing or removing the antibody-dependent cell-mediated cytotoxicity (ADCC) by placing a flexible polypeptide amino acid sequence that reduces the interference on the structural conformation between the structural domains at its two ends.
Thompson et al teaches that binding proteins of the present invention are capable of antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cellular cytotoxicity (CDC), and/or complement fixation [0133]. Thompson et al further teaches wherein the binding protein is modified such that it binds with altered (i.e. either increased or decreased) binding affinity and/or specificity to one or more immunoglobulin specific Fc receptor [0134]. Thompson et al further teaches the modified proteins comprise changes in one or more amino acid sequence(s) in the hinge, CH2, and/or CH3 domain that are responsible for receptor binding affinity and/or specificity [0116]. Thompson et al further teaches typical amino acids suitable to modify binding proteins to have a modified hinge to include Glycine [0028].
Applicant states, “The person skilled in the art would not select glycine, avoid the other amino acids, and include serine to get a flexible amino acid sequence”
Thompson et al teaches typical amino acids suitable to modify binding proteins to have a modified hinge to include Glycine [0028].
Glaser et al teaches for orthogonal modifications are engineered disulfide bridges at position 138 of the CH1 sequence [0161]. Glaser et al further teaches the hinge region typically provides flexibility domains as well as disulfide bridges [0191].
Thompson et al teaches the hinge includes amino acids that restrict motion and the length of the hinge region correlates with the flexibility of the antibody [0008]. Thompson et al further teaches conformational changes permitted by the structure and flexibility of the immunoglobulin hinge region polypeptide sequence may affect the effector functions of the Fc portion of the antibody [0009].
One of ordinary skill in the art, before the effective filing date, would have been motivated to apply Thompson’s method of reducing ADCC/CDC of an antibody by modifying the flexibility of the hinge region of an antibody, with Collier’s method of modifying the hinge region at position 138 which provides flexibility and using the amino acid sequence GGSGGS, with Corey’s method of using ADCC antibodies with fusion proteins, and combined with PD-L1. Furthermore, with Glaser’s method of modifying the hinge region and flexibility of an antibody at position 138. The idea of combining them flows logically from their having been individually taught in the prior art (MPEP 2144.06). Combining prior art elements according to known methods to yield predictable results is an exemplary rationale for a prima facie case of obviousness. MPEP2143. It would have been prima facie obvious to combine the teachings of Thompson, Collier, Corey, and Glaser’s methods for a method of reducing the ADCC/CDC of an antibody by changing the flexibility of the hinge region and change the interference of the structural conformation by using a connecting polypeptide comprising GGSGGS. Motivated because Thompson, Collier and Glaser all teach modifying the flexibility of an antibodies hinge region to change the structural conformations interference.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. 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 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 DENNIS JOHN SULLIVAN whose telephone number is (571)272-0509. The examiner can normally be reached Mon - Fri: 7:30AM - 4:30PM.
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/DENNIS J SULLIVAN/Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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