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 .
Claims Status
In the Amendment filed on 13Jan2025, the Applicant canceled claims 1-39 and 51-59.
In the Amendment filed on 12Dec2025, the Applicant canceled claims 60-62.
Claim(s) 40 is/are currently pending and presented for examination on the merits.
Response to Amendment and Arguments
All previous rejections and/or objections of claim(s) 60-62 are moot in view of claim cancelation.
The rejection(s) of claim(s) 40 under 35 U.S.C. § 112(a) has/have been withdrawn in view of the recent claim amendment filed on 12Dec2025.
As all previously presented rejection(s) and/or objection(s) have been withdrawn, Applicant arguments are not addressed herein.
New Rejections Necessitated by Claim Amendments
Claim Rejections - 35 USC § 112(b)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claim 40 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 40, is rejected on the basis that the claim 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 a composition comprising a TGFBRII binding domain 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: Claim 40 is drawn to a broad number of antibodies with distinct structural similarities, as evidenced by the distinct CDR sequences [e.g., figs. 42, 44, 51-53; figs. ;table 2]. Specifically, (1) claim 40(a) comprises anti-TGFBRII antibodies comprising a Wild-Type (WT) VH sequence paired with mutant (Mut) VL sequences, (2) claim 40(b) comprises anti-TGFBRII antibodies comprising Mut VH sequences paired with a WT VL sequence, and (3) claim 40(c) comprises anti-TGFBRII antibodies comprising Mut VH sequences paired with a Mut VL sequence
The instant specification states that the TGFBRII binding domain(s) of the instant claimed antibodies comprises 6 CDRs: (1) HCDR1-3 and (2) LCDR1-3 [e.g., ¶ 0058-0059, 0063, 0065, 00147-00148, 0150; figs. 19-20, 24-26; table 2]. However, based on Applicant’s disclosure, the claimed antibodies have distinct groupings of conserved sequence/structural characteristics (e.g., 40(a) has a WT VH, or 40(b) has a WT VL, or 40(c) has a single Mut VL) [e.g., instant claim 40; ¶ 0083-0084, 00187, 00197, 00212, 00223; tbls. 42-48, 51]. Because of the differential sequence/structural properties of the instantly claimed antibodies of 40(a-c), they do not have a “single structural similarity”.
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.
Claim Rejections - 35 USC § 112(a)
Claim 40 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for all of the VH/VL pairs of 40(a); the pairing of VL SEQ ID NO: 1867 with a VH of any of SEQ ID NOs: 1863, 1324-1357, 1359-1370, 1372, 1374, 1376-1401, 1404-1414, 1418, and 1421-1430 in 40(b), does not reasonably provide enablement for the pairing of VL SEQ ID NO: 1867 with a VH of any of SEQ ID NOs: 1504, 156-1533, 1535, 1537, 1593, 1595, or 1597 in 40(b), or the pairing of VL of SEQ ID NO: 1659 with a VH of any one of SEQ ID NOs: 1512-1513, 1524, 1594, or 1596. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation."' (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (A) The nature of the invention; (B) The breadth of the claims; (C) The amount of direction provided by the inventor; (D) The existence of working examples; (E) The state of the prior art; (F) The level of predictability in the art; (G) The quantity of experimentation needed to make or use the invention based on the content of the disclosure and (H) The level of one of ordinary skill. While all of these factors are considered, a sufficient amount for amount for a prima facie case are discussed below.
The nature of the invention
Claim 40 is drawn to a composition comprising an anti-TGFBRII antibody.
The breadth of the claims
The claim is broad in that it encompasses antibody VH and VL pairings with no disclosed function testing. Specifically, the Applicant Drawings, Specification, and Tables do not provide evidence that each claimed antibody VH and VL pairing was tested for the retention of TGFBRII antigen binding.
The amount of direction provided by the inventor/the existence of working examples
The examples of the instant disclosure of anti-TGFBRII antibody testing include wild-type (WT) VL and VH variant pairings [e.g., figs. 42A-C, 43, 44A-C, 45-48, 51], and WT VH and VL variant pairings [e.g., ¶ figs. 42C-E, 44C-E].
The examples provided do not demonstrate the testing to ensure TGFBRII binding of all claimed VH/VL pairs. Additionally, the disclosure does not discuss, or demonstrate through working examples, a method that could be used to determine which VH/VL pairings would be expected to retain TGFBRII binding as there is not disclosed testing for each pairing, and there is no evidence that the Applicant conducted testing to determine the critical residue(s) of each CDR for TGFBRII binding.
The state of the art/the level of predictability in the art
At the time of filing, antibody functionality were known to depend on the entire structure, particularly a full complement of six CDRs. It is understood by one of ordinary skill in the art that that mutation to CDRs is unpredictable and that each construct requires function testing.
Sela-Culang, Kunik, and Ofran (Fron. Immuno., Vol. 4, Article 302, Oct. 2013), hereinafter “Sela-Culang”, reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring antibodies have six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition [e.g., pg. 1, abstract; pg. 3, “The Role of CDRs and their Definition”]. A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, that the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized [e.g., pg. 1, “The Motivations for…”].
Further, Herold et al. (Nature Scientific Reports, 7:12276, 25 Sep 2017), hereinafter “Herold”, teaches that it should be emphasized that there is no correlation between experimentally determined change in antibody binding affinity and a given mutation and additionally that no such correlation is expected because antigen binding is “affected by each CDR loop differently” and changes thereto “can in principle affect antigen binding affinity in an unpredictable way” [e.g., pg. 14, ¶ 2]. Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex [e.g., pg. 14, ¶ 3].
Further, at the time of filing, US 2013/0302335 A1 (hereinafter “US335”) taught anti-TGFBRII antibodies were recognized in the art as a promising therapeutic for a variety of diseases [e.g., title, abstract; ¶ 0030-0035]. US335 taught various separate species of anti-TGFBRII antibodies [e.g., ¶ 0210; tbls. 1-2]. Therefore, the prior art demonstrates that the binding of TGFBRII is possible by various anti-TGFBRII antibodies. The prior art does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 in anti-TGFBRII antibody that would allow prediction of CDR residues that specifically bind to TGFBRII antigen.
Thus, making changes to the CDR sequence of an antibody sequence is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations (e.g., mix and match of VH and VL) that would still possess the required function(s).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Studies regarding CDR residue prediction are underway to improve antibody design and development. However, based on the instant disclosure and prior art, there is no known method through which one of ordinary skill in the art would have been able to reliably predict which 6 CDR combinations (e.g., HCDR1-3 and LCDR1-3) would have predictably resulted in an antibody that retains TGFBRII binding. Therefore, in order to practice the invention as claimed, one of ordinary skill in the art would have to perform undue experimentation to (1) test every claimed antibody VH (e.g., comprising HCDR1-3) and VL (e.g., comprising LCDR1-3) combination, or (2) develop a method which accurately predicts 6 CDR combination (e.g., HCDR1-3 and LCDR1-3) antigen binding. Applicant is enabled for anti-TGFBRII antibodies comprising (1) the VH/VL pairs of 40(a), and (2) the pairing of VL SEQ ID NO: 1867 with a VH of any of SEQ ID NOs: 1863, 1324-1357, 1359-1370, 1372, 1374, 1376-1401, 1404-1414, 1418, and 1421-1430 of 40(b).
Conclusion
In view of the Wands factors as discussed above, one of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the instant claimed invention. As such, instant claim 40 was determined to not meet the scope of enablement requirement of 35 USC § 112(a).
Enablement can be met by amending claims 40 to remove the VH/VL pairs that do not have evidence of TGFBRII antigen binding testing (e.g., (A) VL SEQ ID NO: 1867 with a VH of any of SEQ ID NOs: 1504, 156-1533, 1535, 1537, 1593, 1595, or 1597 in 40(b), and (B) the pairing of VL of SEQ ID NO: 1659 with a VH of any one of SEQ ID NOs: 1512-1513, 1524, 1594, or 1596).
Conclusion
No claims are currently allowed.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643