DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2 Applicant's amendment, filed on 07/07/2026, is acknowledged.
3. Claims 1-4, 6, 8, 10-11, 13, 15-19, 23-26, and 28 are pending.
4. Applicant’s election without traverse of Group I, claims 1-4, 6, 8, 10, 11, 13 and 15 directed to FAP binding polypeptide and the CDR 1-3 of SEQ ID NO: 75, 183, 291 and VHH of SEQ ID NO: 399, FAP-FR3-A01, filed on 07/07/2026, is acknowledged.
5. Claims 16-19, 23-26, and 28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
6. Claims 1-4, 6, 8, 10, 11, 13 and 15 are under examination as they read on FAP binding polypeptide and the CDR 1-3 of SEQ ID NO: 75, 183, 291 and VHH of SEQ ID NO: 399, FAP-FR3-A01.
7. Applicant’s IDS, filed 02/27/2024, is acknowledged.
8. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA 35 U.S.C. 112, first paragraph):
(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.
9 Claims 1, 3-4, 6, 8, 10, 11, 13 and 15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 encompasses a broad genus of FAP binding polypeptides comprising mixing and matching up to 108 different VHH CDR1 , CDR2 and CDR3 which is 1083 which is 1,242,432 different FAP binding polypeptides, as well as up to 10% modification in the CDRs (~30 amino acids) which encompasses 320, which is 34,86,784,401 variations in the CDRs.
Claim 3 encompasses a genus of FAP binding polypeptides comprising up missing and matching the CDRs and 10% modification in SEQ ID NO: 399.
Claim 10 encompasses a genus of FAP binding polypeptides comprising up to 10% modification in the CDR1 and up to 10% modification in the polypeptides of SEQ ID NO: 399.
Claims 6, 8, 10, 11, 13, 15 encompass a broad genus of FAP binding polypeptides comprising less than the required 3 CDRs as well as up to 10% modification in the CDRs. The claims encompasses also mixing and matching of CDRs.
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However, there does not appear to be an adequate written description in the specification as-filed of the essential structural feature that provides the recited function of binding FAP. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement make clear that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus.
The specification at [0348] discloses cells were collected from anti-FAP CAR-T library screens. Genomic DNA (gDNA) was extracted using the Blood/Cell Genome DNA Mini kit (Tiangen, DP304-03). 75 ng of gDNA was used for PCT to amplify the CAR region of the library. The amplified region was TA cloned with the TA/Blunt-Zero Cloning kit (Vazyme, C601) and sequenced (example 1).
The specification at pages 43-52 discloses108 anti-FAP antibody VHH clones FAP-FR2-A01, FAP- WO2022133094 FR2-B01, FAP-FR2-C01, FAP- FR2-E01, FAP-FR2-F01, FAP- FR2-G01. FAP-FR2-H01, FAP- FR2-B02, FAP-FR2-C02, FAP- FR2-D02, FAP-FR2-E02, FAP- FR2-H02, FAP-FR2-B03, FAP- FR2-C03, FAP-FR2-D03, FAP- FR2-F03, FAP-FR2-H03, FAP- FR2-B04, FAP-FR2-D04, FAP- FR2-E04, FAP-FR2-G04, FAP- FR2-A05, FAP-FR2-C05, FAP- FR2-D05, FAP-FR2-E05, FAP- FR2-F05, FAP-FR2-G05, FAP- FR2-H05, FAP-FR2-A06, FAP- FR2-B06, FAP-FR2-C06, FAP- FR2-D06, FAP-FR2-E06, FAP- FR2-F06, FAP-FR2-A07, FAP- FR2-B07, FAP-FR2-C07, FAP- FR2-D07, FAP-FR2-E07, FAP- FR2-F07, FAP-FR2-G07, FAP- FR2-H07, FAP-FR2-A08, FAP- FR2-C08, FAP-FR2-D08, FAP- FR2-E08, FAP-FR2-G08, FAP- FR2-A09, FAP-FR2-B09, FAP- FR2-C09, FAP-FR2-D09, FAP- FR2-E09, FAP-FR2-F09, FAP- FR2-H09, FAP-FR2-B10, FAP- FR2-C10, FAP-FR2-D10, FAP- FR2-E10, FAP-FR2-F10, FAP- FR2-G10, FAP-FR2-H10, FAP- FR2-A11, FAP-FR2-C11, FAP- FR2-D11, FAP-FR2-F11, FAP- FR2-G11, FAP-FR2-H11, FAP- FR2-B12, FAP-FR2-C12, FAP- FR2-D12, FAP-FR2-F12, FAP- FR2-G12, FAP-FR2-H12, FAP- FR3-A01, FAP-FR3-B01, FAP- FR3-E01, FAP-FR3-F01, FAP- FR3-H01, FAP-FR3-A02, FAP- FR3-C02, FAP-FR3-D02, FAP- FR3-F02, FAP-FR3-G02, FAP- FR3-A03, FAP-FR3-B03, FAP- FR3-C03, FAP-FR3-D03, FAP- FR3-A04, FAP-FR3-B04, FAP- FR3-E04, FAP-FR3-G04, FAP- FR3-H04, FAP-FR3-D05, FAP- FR3-E05, FAP-FR3-G05, FAP- FR3-H05, FAP-FR3-C06, FAP- FR3-E06, FAP-FR3-F06, FAP- FR3-G06, FAP-FR3-H06, FAP- FR3-A07, FAP-FR3-B07, FAP- FR3-E07, FAP-FR3-F07, and FAP-FR3-G07 VHH regions.
The specification provides 108 anti-FAP sdAb which was not random combinations of VHH i.e., they had specific VHH domain (SEQ ID NO: 325-432). No other VHH domain was provided that share the CDR-H1 of SEQ ID NO: 1-108 or CDR-2 of 109-216 or mixing and matching CDR-H1 of SEQ ID NO: 1-108, CDR-2 of 109-216 and 217-324. The prior art methods do not result in sdAb solely by keeping either CDR-H1 or CDR-H2 or mixing and matching CDR-H1-3 in the VHH defined and randomized the rest of the VHH domains. The prior art indicated that the CDR-H1, CDR-H2 or mixing and matching of different CDR-H-3 form different clone is sufficient to provide FAP binding polypeptides. However, those regions, CDR-H1, CDR-H2 or mixing and matching different CDR-H1-3 form different clones is not solely responsible for binding. The conformation of the other CDRs, as well as framework residues influence binding.
Neither the specification, nor the prior art provides any examples to support the premise that CDR-H1, CDR-H2, CDR-H3 or random combination of different clones of the VHH is solely responsible for antigen binding. The prior art does not support a definition of an nanobody structure solely by defining the CDR-H1, CDR-H2 sequence of a VHH. Accordingly, the disclosed species would not be deemed by one of skill in the art to be representative of the claim scope. The claims do not meet the requirement s of 35 USC 112, first paragraph for written description.
The claims encompass sdAbs in which modification of the amino acids may vary in either or both the CDR-H1, CDR-H2 or CDR-H3, combination thereof of the VHH regions of SEQ ID NOs: 1-432 via addition, deletion, substitution or insertion of one or more amino acids.
The specification discloses only 108 species within the instant claim scope multimillion claimed nanobodies. The instant application encompasses (but does not exemplify) fragments and analogs (deletion/addition/substitution) to the claimed VHH of SEQ ID NOs: 325-432. There is no teaching identifying what amino acids can be varied within the VHH nanobody regions and still retain specific binding member that binds FAP. Brown et al (J. Immuno. 1996 May, 3285-91 at 3290 and Tables 1 and 2) describes how a one amino acid change in the VH CDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region. Vajdos et al. (J. Mol. Biol. 2002, Jul 5, 320(2):415-28 at 416) teach that amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. The scope of the claims encompasses antibodies with VH or VL that encompass variation (addition, deletion, substitution) in their CDRs. The prior art discloses that 6 CDRs as being essential structure of antibody’s binding site, and thus when intact, would provide enough structure to define the antibody’s binding site (structure/function correlation) e.g., where amino acid substitutions can be made so as to change (e.g. 6CDR’s) or retain (e.g., constant or variable framework) antigen binding. Neither the prior art nor applicant's disclosure defines sufficient representative antibodies and/or sufficient structure/function correlation between modifying the VHH regions of the disclosed nanobody and the retention of a specific binding polypeptides that binds FAP to satisfy the WD requirement for the claims.
The claims recite mixing and matching different CDRs from 108 different anti-FAP sdAb clones (SEQ ID NOs: 325-432), wherein the 108 antibodies have different antigen/epitaph binding specificity within FAP protein, different properties including different antibody affinity and sensitivity and different rate of inhibition.
The claims are directed to a possible combination of 1083 which is 1,242,432 different sdAb in addition to up to 10% modifications in the CDRs in claim 1. The specification only describes 108 combinations out several millions of combination. The claims are directed to a genus of anti-FAP sdAb that require mixing and matching between different VHH corresponding CDRs. No such mixing and matching was provided in the specification or the art at the time of filing.
The specification fails to show that all the claimed CDR-H1, CDR-H2 and CDR-H3 of VHH are equal and therefore interchangeable and provide binding specificity of the anti-FAP sdAb. The specification fails to establish that by replacing a CDR-H1 (e.g., clone FAP-FR2-A01, SEQ ID NO: 325) for the corresponding CDR-H1 of any antibody of clones of SEQ ID NO: 326-432 selectivity switch the properties of the replaced CDR in concert with the CDR replacement. It is not clear which binding properties the new replaced CDRs will assume, the donor properties or the acceptor VHH antibody.
Substituting the CDR of an anti-FAP VHH antibody to the corresponding CDR of another anti-FAP VHH antibody has not been shown to lead to an anti-FAP VHH selectivity switch in concert with the substituted CDR. Such teachings were not made part of the specification at the time the invention was made.
With respect to the recitation an antibody which does not comprise all 3 CDRs of the nanobody that is produced by clones of SEQ ID NO: 325-432, the Examiner directs Applicant's attention to the training material given by Bennett Celsa, Example 2: (Ab genus: modified CDR's) slides 34-40. Example 2 of the Training material ((https://www.aipla.org/docs/default-source/committee-documents/bcp-files/2020/uspto-bcp-antibody-slides-final.pdf?sfvrsn=b377f2cc_0) which requires that the claims explicitly recite the binding antigen in addition to all 6 CDR regions for fulfillment of the written description requirements under § 112, 1. Slide 39 indicates that a claim encompasses antibodies with 6 intact CDRs as well as a subgenus of antibodies that encompass up to 10% variation (fragments and/or analogs) in the 6 CDRs lacks written description. Slide 40 provide the conclusion that, a single antibody species would not be deemed by one of skill in the art to be representative of a claim that defines an antibody that binds antigen X comprising at least 90% homology to the 6 CDR of the VH and VL chains.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
10. Claims 1, 3-4, 6, 8, 10, 11, 13 and 15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
Claim 1 encompasses a broad genus of FAP binding polypeptides comprising mixing and matching up to 108 different VHH CDR1 , CDR2 and CDR3 which is 1083 which is 1,242,432 different FAP binding polypeptides, as well as up to 10% modification in the CDRs (~30 amino acids) which encompasses 320, which is 34,86,784,401 variations in the CDRs.
Claim 3 encompasses a genus of FAP binding polypeptides comprising up missing and matching the CDRs and 10% modification in SEQ ID NO: 399.
Claim 10 encompasses a genus of FAP binding polypeptides comprising up to 10% modification in the CDR1 and up to 10% modification in the polypeptides of SEQ ID NO: 399.
Claims 6, 8, 10, 11, 13, 15 encompass a broad genus of FAP binding polypeptides comprising less than the required 3 CDRs as well as up to 10% modification in the CDRs. The claims encompass also mixing and matching of CDRs.
The claims are directed to a broad class of nanobodies was that the class was defined by its function—the ability to bind to FAP. However, the specification did not give the skilled in the art enough information to choose candidate antibodies from the several millions of options and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
The specification discloses 108 species of anti-FAP nanobodies of SEQ ID NOs: 325-432; while the claims are directed to a genus of millions anti-FAP nanobodies.
In Sanofi-Aventisub, the Federal Circuit relied on its prior precedential opinions when determining whether the full scope of a genus was enabled. These decisions included McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091 (Fed. Cir. 2020) (hereafter McRO); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380 (Fed. Cir. 2013) (hereafter Wyeth); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019) (hereafter Enzo); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149 (Fed. Cir. 2019) (hereafter Idenix).
The Federal Circuit, citing McRO, provided guidance on the application of enablement to genus claims, holding that “[a]lthough a specification does not need to describe how to make and use every possible variant of the claimed invention, when a range is claimed, there must be reasonable enablement of the scope of the range.” Sanofi-Aventisub, 987 F.3d at 1085 (internal quotations omitted). Additionally, the Federal Circuit characterized Wyeth as holding “that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality.” Id. at 1086. Similarly, the Federal Circuit characterized Enzo as holding “that the specification failed to teach one of skill in the art whether the many embodiments of the broad claims would exhibit that required functionality.” Id. Finally, the Federal Circuit characterized Idenix as affirming “the district court's determination that the claims had both structural and functional limitations, and that undue experimentation would have been required to synthesize and screen the billions of possible compounds because, given a lack of guidance across that full scope, finding functional compounds would be akin to finding a `needle in a haystack.' ” Id.
This case is akin to the issue in Sanofi-Aventisub, the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. While the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class that included “a `vast' number of additional antibodies” that Amgen had not described by their amino acid sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire class of antibodies by their function, which was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. In the instant case, the specification discloses only two species that performed the claimed function by their amino acid sequences, with the claimed genus of 9,905 different anti-hANGPTL3 antibodies. The instant claims are directed to a class of anti-hANGPTL3 antibodies that included “a `vast' number of additional antibodies” that the instant specification fails to describe their amino acid sequences.
The scope of the instant claims encompassed millions of nanobodies and that it was necessary to first generate and then screen each candidate to determine whether it met the functional limitations. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
The claims simply direct skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the two antibodies they elected to disclose and that “[u]nder Amgen, such random trial-and-error discovery, without more, constitutes unreasonable experimentation that falls outside the bounds required by § 112(a).” Id. at *8, *10.
Amgen attempted to claim an entire class of compounds by their function, namely antibodies that bind to the “sweet spot” of PCSK9 thereby inhibiting it from binding to LDL, while only describing 26 amino acid sequences in its specification. The two processes, the “roadmap” and “conservative substitution” did not save Amgen. According to the Court, these amounted to “little more than two research assignments” which forced scientists to conduct “painstaking experimentation” to see what worked. (citing Incandescent Lamp). The Court therefore held that Amgen’s specification did not enable the claims.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
11. Claim 2 (75) is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. It is noted that claim 2 recites unreasonable number of sequences to be searched. Given that the Office limits up to 25 ABSS query sequences search per application, the Examiner suggests that Applicants limits the claims to 25 sdAb of their choice. Also, the Examiner suggest that the preamble “a fibroblast activation protein (FAP) binding polypeptide“ of the claim be change to “a single domain antibody (sdAb) that specifically binds to a fibroblast activation protein (FAP) comprising . . .“ SEQ ID NOs: 75, 183, 291 and 399 are free from prior art.
12. The art made of record and not relied upon is considered pertinent to applicant's disclosure:
US 20260124303 A1
The `303 claims invariant natural killer T (iNKT) cells comprising a chimeric antigen receptor (CAR) that specifically binds fibroblast activation protein (FAP).
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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January 3, 2024
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644
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