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 08/02/2023, is acknowledged.
3. Claims 1-8, 10-11, 14-16, 19-21 ,24, 26, 28 and 30 are pending.
4. Applicant’s election without traverse of Group I, claims 1-8, 10-11, 16, 24 and 28, directed to an anti-glypican-3 (GPC3) antibody and the following species:
(a) VH64 of SEQ ID NO: 611 comprising the CDRs of SEQ ID NO: 258, 259 and 260 + VL72 of SEQ ID NO: 609 comprising the CDR of SEQ ID NO: 614, 502 and 503.
(b) VH79 of SEQ ID NO: 635 comprising the CDRs of SEQ ID NO: 303, 304 and 305+ VL76 of SEQ ID NO: 629 comprising the CDRs of SEQ ID NO: 637, 532 and 533; and
(c) VH82 of SEQ ID NO: 28 comprising the CDRs of SEQ ID NO: 312, 313 and 314 and VL55 of SEQ ID NO: 62 comprising the CDRs of SEQ ID O: 537, 538 and 539.
filed on 3/23/2026, is acknowledged.
5. Claims 14-15, 19-21, 26, 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
6. Claims 1-8, 10-11, 16, 24 and 28 are under examination as they read on an anti-glypican-3 (GPC3) antibody and the following species:
(a) VH64 of SEQ ID NO: 611 comprising the CDRs of SEQ ID NO: 258, 259 and 260 + VL72 of SEQ ID NO: 609 comprising the CDR of SEQ ID NO: 614, 502 and 503.
(b) VH79 of SEQ ID NO: 635 comprising the CDRs of SEQ ID NO: 303, 304 and 305 + VL76 of SEQ ID NO: 629 comprising the CDRs of SEQ ID NO: 637, 532 and 533; and
(c) VH82 of SEQ ID NO: 28 comprising the CDRs of SEQ ID NO: 312, 313 and 314 and VL55 of SEQ ID NO: 62 comprising the CDRs of SEQ ID O: 537, 538 and 539.
7. Applicant’s IDS, filed 08/02/2023, is acknowledged.
8. The following is a quotation of 35 U.S.C. 112(b) (Pre AIA , 35 U.S.C. 112, second paragraph):
(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.
9. Claims 1-8, 10-11, 16, 24 and 28 are rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
(i) The recitation "preferably ..." in claims 1-3, 5, 7, 11, 16 is indefinite because the narrow range within the broad range using the term “preferably” renders the claim indefinite.
(ii) The recitation “having a sequence of amino acid residues 524-563 of glypican-3” in claim 10 is indefinite, it is indefinite to recite amino acid positions without structural features for the comparison. It is suggested to recite the SEQ ID NO:586 of glypican-3 to overcome the rejection.
(iii) the recitation “VH single domain antibodies”, “complementarity determining region (CDR) fragments”, “domain antibodies” and “minimal recognition units of antibodies” in claim 7 and “fully human antibody” in claim 8 are ambiguous because the antibody is derived from mice clones. It is not clear how the murine antibodies comprising 6 CDRs would be “VH single domain antibodies”, “complementarity determining region (CDR) fragments”, “domain antibodies” and “minimal recognition units of antibodies” “fully human antibody”.
(iv) the recitation “heteropolyantibody or a heteroconjugate antibody” in claim 16 is indefinite. It is not clear what are those antibodies are.
10. 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.
11. Claims 1-8, 10-11, 16, 24 and 28 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 anti-GPC3 antibodies comprising up to the full length VH-CDRs modification and VL-CDRs modifications; as well as mixing and matching of different CDRs from different anti-GPC3 antibodies from different clones.
Claim 2 encompasses a broad genus of anti-GPC3 antibodies comprising up to the full length VH-CDRs modification and VL-CDRs modifications; as well as mixing and match of different sets of VH-CDR1-3 with different sets of VL-CDR1-3 from different clones.
Claims 3-4 encompass a genus of anti-GPC3 antibodies comprising up to 20% modifications in the VH-CDRs and/or VL-CDRs.
Claim 5 encompasses a genus of anti-GPC3 antibodies comprising antibodies comprising up to 20% modification or up to 20 amino acid modifications in the VH and/or VL of SEQ ID NOs: 28/62, 611/609, 635/629.
Claim 6 encompasses a genus of anti-GPC3 antibodies comprising antibodies comprising up to 30% modification in the VH and/or VL of SEQ ID NOs: 28/62, 611/609, 635/629.
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 GPC3. 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 discloses the generation of mouse antibodies against GPC3, then selected better binders and converted several into humanized versions. The resulting antibodies can recognize human, monkey, and in some cases mouse GPC3 with high affinity.
The specification discloses the results showed that both the antibodies Y035 and T2-23 had good binding activity with the human GPC3 protein and the monkey GPC3 protein; and the Y035 did not bind to the murine GPC3 protein, and the T2-23 bound well to the murine GPC3 protein. The IgG subtype control was human IgG1 [0210].
The results showed that the T2-23 could not bind to the polypeptide GC3pep, while the Y035 could bind to the polypeptide GC3pep, indicating that the polypeptides with binding activity have been prepared [0211].
The results showed that HepG2 cells could bind to both the Y035 and the T2-23 [0212].
The results indicated that 1C3, 2B5, and 3E9 were cell strains with high-level expression of human GPC3 [0213].
The specification under example 2 discloses the preparation of hybridoma antibody against GPC3. Polypeptide GC3pep coupled to a carrier protein (KLH) was produced, i.e., polypeptide GC3pep-KLH (AELAYDLDVDDAPGNSQQATPKDNEISTFHNLGNVHSPLKC-KLH, SEQ ID NO: 586). The obtained 48 clones were subjected to ELISA and data analysis according to the method described in Example 1 (A). An ELISA plate reader was used to read OD450 nm values, with results for binding activity of GPC3 human-murine chimeric antibodies with the human GPC3 protein as shown in FIG. 11 and Table 15. The results showed that a total of 34 antibodies bound well to the human GPC3 protein, including 20 antibodies in the F1 series, 7 antibodies in the F2 series, 3 antibodies in the F3 series, and 4 antibodies in the F4 series (Table 1) [0222].
The results showed that the 8 antibodies F1.2.14, F1.21.8, F1.42.8, F1.111.11, F1.145.22, F2.169.2. F2.152.3, and F4-13.7 bound well to the murine GPC3 protein, the antibody F4-26.1 bound weakly to the murine GPC3 protein, and the remaining antibodies did not bind to the murine GPC3 protein [0224]. The results showed that the antibodies F1.78.24. F1.83.6. F1.92.17 and F1.110.24 weakly bound to the monkey GPC3 protein, and the remaining antibodies bound well to the monkey GPC3 protein [0225]. The results showed that most of the humanized antibodies bound well to the human GPC3 protein [0258]. The results showed that antibodies of hAb001 series bound well to the murine GPC3 protein, while the remaining antibodies did not bind to the murine GPC3 protein [0260].
The claims recite mixing and matching different CDRs from 102 different anti- GPC3 antibodies clones, wherein the 102 antibodies have different properties including different antibody affinity and sensitivity (Kd- [0180]), different epitope recognition, different cross reactivity. Claim 1 directed to a possible combination of 1,126,162,419,264 (1026) different antibodies in claim 1. The specification only describes 102 combinations out 1,126,162,419,264 combinations. The claims are directed to a genus of anti-GPC3 antibodies that require mixing and matching between different VH and VL corresponding CDRs. No such mixing and matching was provided in the specification or the art at the time of filing. Claim 2 encompasses mixing and matching of 102 VH with 68 VL which would result in (102X68) 6,936 unique paired combinations.
The specification provides 102 anti-GPC3 antibodies including VH64+VL72, VH82+VL55 and VH79+VL76, which were not random combinations of VH and VL i.e., they had specific VH domain (SEQ ID NO: 611, 28 and 635 ) paired with specific VL domain (SEQ ID NO: 609, 62 and 629, respectively). No other VH/VL domain was provided that mix the CDRH1 of SEQ ID NO: 258312, 303, CRRH2 of SEQ ID Nos:258, 313, 304 or CDRH3 of SEQ ID NO: 260, 313, 305 or CDRL1 of SEQ ID NO: 614, 537, 637, CDRL2 of SEQ ID NO: 502, 528, 532 and CDRL3 of SEQ ID NO: 503, 539, 533. The specification discloses only three species within the instant claim scope. The instant application encompasses (but does not exemplify) fragments and CDRs modification up to 20% (deletion/addition/substitution) to the claimed HCDRs and LCDRs of SEQ ID NOs: : 258, 259 and 260+614, 502 and 503; 303, 304 and 30+ 637, 532 and 533; 312, 313 and 314, 537+ 538 and 539 and VH of SEQ ID NO: 611, 28 and 635 and VL of SEQ ID NO: 609, 62 and 629. There is no teaching identifying what amino acids can be varied within the VH-CDRs and/or VL-CDRs antibody regions and still retain antibody or fragments capable of binding space domain of GPC3. 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 VLCDRs or VHCDRs regions of the disclosed antibody and the retention of a specific binding antibody that binds the Olfml-3 to satisfy the WD requirement for the claims.
Neither the specification, nor the prior art provides any examples to support the premise of mixing and matching a HCDR or LCDR of the VH/VL of different antibodies would result in antigen binding. The prior art does not support a definition of an antibody structure by mixing and matching the HCDR1-3 sequence of a VH and/or LCDR of sequence of a VL and result in functional anti-GPC3 antibody. The specification fails to show that all HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3 of the anti-GPC3 antibodies, VH64+VL72, VH82+VL55 and VH79+VL76 are equivalent. The specification fails to establish that by replacing at least one CDR of VH64+VL72 antibody with another CDR from VH82+VL55 and VH79+VL76, maintains GPC3 binding. Mixing and matching different the CDRs from different anti-GPC3 antibodies has not been shown to lead to GPC3 binding. Such teachings were not made part of the specification at the time the invention was made.
It is unlikely that antibodies or fragments thereof as defined by the claims which may contain less than the full complement of CDRs from the heavy and light chain variable regions of the VH64+VL72, VH82+VL55 and VH79+VL76 antibody fused to framework sequence, have the required binding function. The specification provides no direction or guidance regarding how to produce antibodies as broadly defined by the claims. Undue experimentation would be required to produce the invention commensurate with the scope of the claims from the written disclosure alone. Further, the specification does not teach that a functional antibody can be obtained by replacing the CDR regions of an acceptor antibody with the less than all the 6 CDRs sequences of a donor antibody.
With respect to the recitation an antibody which does not comprise all 6 CDRs of the antibodies VH64+VL72, VH82+VL55 and VH79+VL76, 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.
Regarding the amino acid substations in variable region, one skilled in the art have recognized challenge and trade-offs once it is applied in antibody. Rabia et al (Biochem Eng J. 2018 September 15; 137: 365-374) states that optimize antibody properties (affinity, specificity, stability, solubility and effector functions) with amino acid substitutions is challenge and is always trade-offs and states that an outstanding challenge in the field is that optimizing properties such as antibody affinity can lead to defects in other properties such as antibody stability, specificity and solubility. The resulting trade-offs between improvements in some antibody properties and reductions in others highlight that they are often interdependent and cannot be easily separated (introduction). Rabia et al further state given that the maximal chemical diversity of antibody CDRs is unimaginably large (>1078 antibody variants based on 20 different amino acids at ~60 sites in the CDRs), it is extremely challenging to define the sequence determinants of antibody specificity (para 2).
Kranz et al. (Proc. Natl Acad. Sci, USA, 78(9):5807-5811, 1981) showed that in mixing heavy and light chains from six monoclonal anti-fluorescyl antibodies, heterologous heavy and light chain mixtures did not form anti-fluorescyl active sites (p. 5809, col. 1, first part of second paragraph). In another experiment (supra, p. 5809, col. 1, third paragraph), “Of the 30 possible heterologous H and L chain combinations, 13 did not reassociate within detectable limits..., 13 reassociated but with less affinity than the homologous association,.. and 4 associated with greater affinity than the homologous reassociation....” In the instant claims, not just the heavy and light chains are mixed, but CDRs from different antibodies may be mixed. Herold et al. (Scientific Reports, 7:12276, DOI:10.1038/s41598-01 7-12519-9, Sept. 2017, p. 2, end of second paragraph), looked at VH/VL interfaces and how changes effected antigen binding and found, “Our results on the effects of mutations on domain structure, stability, association and antigen binding together with CDR exchange experiments reveal complex relationships between structural and functional properties within the VL and VH domains.” It was discussed that (p. 11, start of 3rd paragraph), “The relationship between structure, stability and binding affinity of VH and VL is still unclear. This is an important aspect for understanding antibody architecture both as the basis of our immune system and also in the context of the engineering of antibodies for therapeutic purposes. In this context, it was found that in mutants an increase in affinity is often accompanied by a decrease in stability and vice versa - and these consequences are difficult to predict.” The reference concludes (p. 14, end of 2nd paragraph and 3rd paragraph), “[B]inding to the antigen is affected by each CDR loop differently and changes in loop mobility can in principle affect antigen binding affinity in an unpredictable way... Taken together our data indicate that multiple determinants regulate the VH/VL association and the affinity for the antigen. The interplay between interface interactions and CDRs turned out to be complex with mutual influences on VH/VL association and antigen binding.” Herold et al. and Kranz et al. illustrate the unpredictability of mixing antibody VH/VL chains (and implicitly their CDRs) with respect to binding properties.
"When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (fed. Cir. 2005)) (emphasis added).
"A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
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.
12. Claims 1-8, 10-11, 16, 24 and 28 are 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 an anti-Glypican-3 antibody or antigen-binding fragment thereof comprising (a) VH64 of SEQ ID NO: 611 comprising the CDRs of SEQ ID NO: 258, 259 and 260 + VL72 of SEQ ID NO: 609 comprising the CDR of SEQ ID NO: 614, 502 and 503.
(b) VH79 of SEQ ID NO: 635 comprising the CDRs of SEQ ID NO: 303, 304 and 305 + VL76 of SEQ ID NO: 629 comprising the CDRs of SEQ ID NO: 637, 532 and 533; and
(c) VH82 of SEQ ID NO: 28 comprising the CDRs of SEQ ID NO: 312, 313 and 314 and VL55 of SEQ ID NO: 62 comprising the CDRs of SEQ ID O: 537, 538 and 539,
does not reasonably provide enablement for an anti-Glypican-3 antibody or antigen-binding moiety recited in claims 1-8, 10-11, 16, 24 and 28. 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.
Claim 1 encompasses a broad genus of anti-GPC3 antibodies comprising up to the full length VH-CDRs modification and VL-CDRs modifications; as well as mixing and matching of different CDRs from different anti-GPC3 antibodies from different clones.
Claim 2 encompasses a broad genus of anti-GPC3 antibodies comprising up to the full length VH-CDRs modification and VL-CDRs modifications; as well as mixing and match of different sets of VH-CDR1-3 with different sets of VL-CDR1-3 from different clones.
Claims 3-4 encompass a genus of anti-GPC3 antibodies comprising up to 20% modifications in the VH-CDRs and/or VL-CDRs.
Claim 5 encompasses a genus of anti-GPC3 antibodies comprising antibodies comprising up to 20% modification or up to 20 amino acid modifications in the VH and/or VL of SEQ ID NOs: 28/62, 611/609, 635/629.
Claim 6 encompasses a genus of anti-GPC3 antibodies comprising antibodies comprising up to 30% modification in the VH and/or VL of SEQ ID NOs: 28/62, 611/609, 635/629.
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.
The claims are directed to a broad class of antibodies was that the class was defined by its function—the ability to bind to GPC3. However, the specification did not give the skilled in the art enough information to choose candidate antibodies from the 1,126,162,419,264 (1026) 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.”
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 102 species that performed the claimed function by their amino acid sequences, with the claimed genus of 1,126,162,419,264 (1026) different anti-GPC3 antibodies and up to 20% modification of each and every CDRs in those antibodies. The instant claims are directed to a class of anti-GPC3 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 1,126,162,419,264 (1026) of antibodies and up to 20% variation in their CDRs 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.
13. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
14. Claims 1-4, 7-8, 10, 16, 24 and 28 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 20230088461.
The `461 publication teaches mouse anti-GPC3 monoclonal antibody VL region (LAb19303), SEQ:73 comprising claimed VL-CDR1-3 of SEQ ID NOs: 637-532-533 having two substitutions (see first alignment below) and VH region (LAb19303), SEQ:63 comprising claimed VH-CDR1-3 of SEQ ID NO: 303-304-305.
Qy 1 RSSQTFVHSNANTYLQ---------------KVSNRFS---------------------- 23
||||:||||| ||||| |||||||
Db 24 RSSQSFVHSNGNTYLQWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRV 83
Qy 24 ----------FQGSHVPYT 32
|||||||||
Db 84 EAEDLGVYYCFQGSHVPYT 102
Mouse anti-GPC3 monoclonal antibody VH region (LAb19303), SEQ:63 comprising 5 substitutions.
Qy 1 DYEIH--------------AIDPKTGNTAYNQKFMG------------------------ 22
|||:| ||||:|| ||||||| |
Db 31 DYEMHWVKQTPVHGLEWIGAIDPETGATAYNQKFKGKATLTADKSSSTAYMELRSLTSED 90
Qy 23 --------YFSFAY 28
|:||||
Db 91 TAVYYCTRYYSFAY 104
The `461 publication teaches affinity anti-human GPC3 antibodies. The affinity of GPC3 to antibodies was summarized in Table 6, wherein the Lab19303 KD is 1.38E-08.
The kits or article of manufacture may include multiple unit doses of the pharmaceutical composition and instructions for use, packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies [0469].
The `461 publication teaches a fusion protein, immunoconjugate, and a multispecific binding molecule) comprising the antibody provided herein and a pharmaceutically acceptable excipient. [0476]. [0290] The immunuoconjugates or ADCs herein contemplate, but are not limited to such conjugates prepared with cross-linker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfone)benzoate) which are commercially available [0286]- [0289]
The reference teachings anticipate the claimed invention.
15. Claims 1-4, 7-8, 10, 16, 24 and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2016049459.
The `459 publication teaches human glypican-3 chimeric antigen receptor protein of published SEQ ID NO: 14 comprising the VH-CDRs of SEQ ID NO: 312, 313 and 314 and the VL-CDRs of SEQ ID NO: 537, 538 and 539. The published VH-CDRs sequence comprising substitutions in the VH CDR2 and CDR3, wherein the antibody is bispecific antibody constructs [0140]. A kit comprising a GPC3 CAR construct [0141]. The antibody also may be conjugated to a drug or toxin (chemotherapeutic, radionuclide, ricin A chain, cholera toxin, pertussis toxin, etc.) and serve merely as a targeting agent [0154]. GPC3 CAR constructs together with a pharmaceutically acceptable carrier or excipient [0136].
Alignment of published SEQ ID NO: 14 with claimed SEQ ID NO: 537, 538 and 539.
Query Match 85.4%; Score 144.3; Length 457;
Best Local Similarity 40.5%;
Matches 32; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 RSSQSLVHSNGNTYLH---------------KVSNRFS---------------------- 23
|||||||||||||||| |||||||
Db 173 RSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRV 232
Qy 24 ----------SQNTHVPPT 32
|||||||||
Db 233 EAEDLGVYFCSQNTHVPPT 251
Alignment of published SEQ ID NO: 14 with claimed SEQ ID NO: 312-313-314.
Query Match 67.8%; Score 106.4; Length 457;
Best Local Similarity 29.7%;
Matches 22; Conservative 5; Mismatches 1; Indels 46; Gaps 2;
Qy 1 DYEMH--------------AIDPETGNTAYIQKFKG------------------------ 22
||||| |:||:||:||| |||||
Db 50 DYEMHWVKQTPVHGLKWIGALDPKTGDTAYSQKFKGKATLTADKSSSTAYMELRSLTSED 109
Qy 23 --------FYSYSH 28
||||::
Db 110 SAVYYCTRFYSYTY 123
The reference teachings anticipate the claimed invention.
The `782 publication teaches anti-GPC3 humanized scFv VL region, SEQ:15 comprising claimed the VL-CDRs of SEQ ID NO: 537, 538 and 539.
Query Match 85.4%; Score 144.3; Length 112;
Best Local Similarity 40.5%;
Matches 32; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 RSSQSLVHSNGNTYLH---------------KVSNRFS---------------------- 23
|||||||||||||||| |||||||
Db 24 RSSQSLVHSNGNTYLHWYQQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRV 83
Qy 24 ----------SQNTHVPPT 32
|||||||||
Db 84 EAEDVGVYYCSQNTHVPPT 102
16. No claim is allowed.
17. The following anti-GPC3 antibodies are free from prior art:
(a) VH64 of SEQ ID NO: 611 comprising the CDRs of SEQ ID NO: 258, 259 and 260 + VL72 of SEQ ID NO: 609 comprising the CDR of SEQ ID NO: 614, 502 and 503.
(b) VH79 of SEQ ID NO: 635 comprising the CDRs of SEQ ID NO: 303, 304 and 305 + VL76 of SEQ ID NO: 629 comprising the CDRs of SEQ ID NO: 637, 532 and 533; and
(c) VH82 of SEQ ID NO: 28 comprising the CDRs of SEQ ID NO: 312, 313 and 314 and VL55 of SEQ ID NO: 62 comprising the CDRs of SEQ ID NO: 537, 538 and 539,
18. 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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May 26, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644
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