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 .
Response to Amendment
The Amendments and Remarks filed 03/02/2026 in response to the Office Action of 10/01/2025 are acknowledged and have been entered.
Claims 1-5, 9, 14, 20-21, 23, 25-26, 29-32, 34 and 36-38 are currently pending.
Claims 37 and 38 are new.
Claims 1, 5, 9, 14, 20-21, 23, 25, 29-30 and 32 have been amended by Applicant.
Claims 1-5, 9, 14, 20-21, 23, 25-26, 29-32, 34 and 36-38 are currently under examination in the instant Office Action
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
This Office Action contains new rejections necessitated by amendments.
Objections - Withdrawn
Given that Applicant has amended the drawings, the objections to the drawings have been withdrawn.
Given that Applicant has amended the drawings and specification to include sequence identifiers, as well as provided a new Sequence Listings file, the objections to the Nucleotide and/or Amino Acid Sequence Disclosures have been withdrawn.
Given that Applicant has amended the specification, all but one of the objections to the specification have been withdrawn. See below for maintained specification objection.
Claim Objections - Withdrawn
Given that Applicant has amended claims 1-5, 9, 14, 19, 21, 29-32, 34 and 36, the objections to said claims have been withdrawn.
Claim Rejections Withdrawn
Given that Applicant has amended claims 5, 14, 21 and 25, and cancelled claim 19, the rejection of said claims under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), second paragraph has been withdrawn.
Given that Applicant has cancelled claim 19, the written description rejection of said claim under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, has been withdrawn.
The enablement rejection of claims 1, 3, 5, 9, 14, 19-21, 23, 25-26, 29-32, 34 and 36 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding binding domains with CDRs that are too short or incomplete in terms of length that provides for antigen binding has been withdrawn. This is because the specification provides sufficient evidence for binding of the fusion protein comprising in the first binding domain: vhCDR1, vhCDR2, vhCDR3 of SEQ ID NOs: 4, 5, 6 respectively, and vlCDR1, vlCDR2 and vlCDR3 of SEQ ID NOs: 7, 8 and 9 respectively; and comprising in the second binding domain: vhCDR1, vhCDR2, vhCDR3 of SEQ ID NOs: 10, 11, 12 respectively, and vlCDR1, vlCDR2 and vlCDR3 of SEQ ID NOs: 13, 14 and 15 respectively, to various target proteins in a number of cancer cell lines.
Given that Applicant has amended claims 29-32, 34 and 36, the enablement rejection of said claims under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding a method for treating just any disease or any cancer or glioblastoma has been withdrawn.
Given that Applicant has amended claims 20-21, 23, 25-26, the enablement rejection of said claims under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding non-isolated nucleic acids, non-isolated expression cassettes, and non-isolated adenoviral vectors has been withdrawn.
Given that Applicant has cancelled claim 19, the rejection of said claim under 35 U.S.C. 103 as being unpatentable over Takeuchi (Journal of Immunological Methods Volume 270, Issue 2, 15 December 2002, Pages 199-209) in view of Czajkowsky (EMBO Mol Med (2012) 4, 1015–1028) and Kimura and Finn (Expert Opin. Biol. Ther. (2013) 13(1):35-49). has been withdrawn.
Specification Objection - Maintained
The disclosure remains objected to because it still contains an embedded hyperlink and/or other form of browser-executable code: http://vbase2.org/ (Pg. 19 line 4).
Claim Rejections - 35 USC § 112(b) - Maintained
Claim 23 remains rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), second paragraph, because the term “preferably” in line 3 and the phrase “even more preferably” in line 5 remain recited in the claim even though Applicant cited in their Remarks that these have been removed.
Claim Rejections 35 U.S.C.112(a) – Maintained and New
Claims 1, 3, 5, 9, 14, 20-21, 23, 25-26, 29-32, 34 and 36 remain rejected and claims 37 and 38 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.
Response to Arguments
In the reply of 03/02/2026, Applicant cites that the written description requirement of 35 U.S.C. § 112(a) is satisfied when the description in the specification allows a person of ordinary skill in the art to recognize that the inventor invented what is claimed. Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1562-63 (Fed. Cir. 1991) (citing In re Gosteli, 872 F.2d 1008, 1012 (Fed. Cir. 1989)). The written description requirement does not require recitation of each and every species within a genus. M.P.E.P. § 2163 ("Description of a representative number of species does not require the description to be of such specificity that it would provide individual support for each species that the genus embraces."). The specification satisfies the written description requirement when "'the essence of the original disclosure' conveys the necessary information 'regardless of how it' conveys such information, and regardless of whether the disclosure's 'words [a]re open to different interpretation[s]."' Inphi Corp. v. Netlist, Inc., 805 F.3d 1350, 1353 (Fed. Cir. 2015) (citing In re Wright, 866 F.2d 422, 424-25 (Fed. Cir. 1989)).
Applicant also cites that the Office alleged that the specification does not adequately describe the genus of fusion proteins comprising CDRs with 90% sequence identity to the referenced sequences. Applicant respectfully disagrees. The rejection is based, at least in part, on the assertion that "Applicant has disclosed only one species for the first binding domain and one species for the second binding domain, with the potential of three more species that have selective binding to Neu5Aca2-3Galp1-3GalNAca-R," (see Action, page 19), with the Office concluding that the disclosure is not sufficient to demonstrate possession of the entire genus of claim 1. The amendments to claim 1 serve to characterize the claimed genus via both structural features, where the fusion protein comprises CDRs with 90% identity to the SEQ ID NOs referenced in the claims, and via functional features, the capacity to bind Neu5Aca2-3Galp1-3GalNAca-R. One of ordinary skill in the art would recognize that Applicant was in possession of the claimed genus at the time of filing. The specification provides the full binding sequences of the fusion protein, including the complete variable heavy chain and variable light chain domain sequences (SEQ ID NOs: 16-19) and the full fusion protein sequence (SEQ ID NO: 23). The specification provides the Kabat numbering and location of the CDR sequences, teaching that the CDR regions are located at amino acid residues 23-24 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in the light chain variable region, and 31-35B (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in the heavy chain region. See specification, page 15 lines 27-31. The at least 90% sequence identity feature defines a structurally limited genus centered around the disclosed sequences which is further defined functionally.
Examiner’s Response: The arguments found in the Reply of 03/02/2026 have been carefully considered but are not deemed persuasive.
In the instant case, the claims are inclusive of a genus of fusion proteins comprising a first binding domain comprising recited SEQ ID NO(s) for the VHCDRs and VLCDRs, a second binding domain comprising recited SEQ ID NO(s) for the VHCDRs and VLCDRs, and a human Fc domain (Fc), capable of selectively binding Neu5Acα2-3Galβ1-3GalNAcα-R, as well as fusion proteins comprising at least 90% sequence identity variants in the CDRs of both binding domains. Further in claim 3, the genus of the fusion protein also includes those comprising sequences comprising at least 90% sequence identity in the VH and VL domains of both binding domains. As such, the 90% sequence identity VH and VL variants means that there could be mutations in and around the VHCDRs and VLCDRs. However, the written description in this case only sets forth three antibody clones on Pg. 45 lines 26-29 and Pg. 46 lines 15-16 that are capable of forming immune complexes with sialosylated glycosphingolipids and sialated glycoproteins as well as their independent constituent monosaccharide sugars Neu5Ac, GalNac and Gal. The three clones are Clone 1: 7F11.B9 Isotype Ig1 k, Clone 2: 2G7.A8 Isotype Ig1 k, and Clone 3: 6H5.C10 Isotype Ig1 k (Pg. 46 lines 15-16). In fact, the specification only discloses one fusion protein species generated using humanized clone 1 and clone 2 (2G7.A8 mAb and 7F11.B9 mAb) (see Example 5 Pg 50-51). Therefore, the specification does not disclose, and the art does not teach, the genus of fusion protein comprising a first binding domain and a second binding domain where each of the domains are capable of selectively binding Neu5Acα2-3Galβ1-3GalNAcα-R as broadly encompassed in the claims when only one species has been disclosed.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common to that genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.” The inventions at issue in Lilly were DNA constructs per se, the holdings of that case is also applicable to claims such as those at issue here.
The instant specification fails to provide sufficient descriptive information, such as definitive structural features that are common to the genus. That is, the specification provides neither a representative number of fusion proteins that encompass the genus that comprises a first binding domain and a second binding domain where each of the domains are capable of selectively binding Neu5Acα2-3Galβ1-3GalNAcα-R, nor does it provide a description of structural features that are common to the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus. “[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.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
Since the disclosure fails to describe common attributes or characteristics that adequately identify members of the genus, and because the genus is highly variant, the disclosure of one species in the specification is insufficient to describe the genus. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as broadly claimed.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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). As discussed above, even though Applicant may propose methods of screening for possible members of the genus, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolation. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. See Ariad, 94 USPQ2d at 1161; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Applicant is reminded that Vas-Cath makes clear that the written descriptiNeu5on provision of 35 U.S.C. §112 is severable from its enablement provision (see page115.
Claim Rejections 35 U.S.C.112(a) – Maintained
Claims 1, 3, 5, 9, 14, 20-21, 23, 25-26, 29-32, 34 and 36 remain rejected and claims 37 and 38 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a fusion protein, capable of selectively binding Neu5Acα2-3Galβ1-3GalNAcα-R, which comprises:
(a) a first binding domain comprising: a VH1CDR1 consisting of SEQ ID NO: 4; a VH1CDR2 consisting of SEQ ID NO: 5; and a VH1CDR3 consisting of SEQ ID NO: 6; and a VL1CDR1 consisting of SEQ ID NO: 7; a VL1CDR2 consisting of SEQ ID NO: 8; and a VL1CDR3 consisting of SEQ ID NO: 9; and (b) a second binding domain comprising: a VH2CDR1 consisting of SEQ ID NO: 10; a VH2CDR2 consisting of SEQ ID NO: 11; and a VH2CDR3 consisting of SEQ ID NO: 12; and a VL2CDR1 consisting of SEQ ID NO: 13; a VL2CDR2 consisting of SEQ ID NO: 14; and a VL2CDR3 consisting of SEQ ID NO; 15, or
VH1 that comprises SEQ ID NO:16, VL1 that comprises SEQ ID NO: 18, VH2 that comprises SEQ ID NO:18 and VL2 that comprises SEQ ID NO: 19;
does not reasonably provide enablement for fusion proteins with at least 90% identity to the respective CDR SEQ ID NO(s); or for fusion proteins with at least 90% identity to the respective VH and VL SEQ ID NO(s). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to perform the process of the invention commensurate in scope with these claims.
Response to Arguments
In the reply of 03/02/2026, Applicant cites that the enablement requirement of Section 112(a) requires that the disclosure contain sufficient information regarding the subject matter of the claims as to permit or enable one skilled in the pertinent art to make and use the claimed invention without undue experimentation. M.P.E.P. § 2164.01. Here, the ordinary skilled practitioner would have appreciated that Applicant invented what is claimed and would be able to make and use the instantly claimed invention without undue experimentation.
Applicant also cites that engineering of the defined CDR sequences is something which the person of ordinary skill would be capable of, using their knowledge of the field and the teaching of the specification in terms of the sequences and functional limitation. The Office acknowledged that the level of skill of one skilled in the art is high (see Action, page 27), and thus engineering of defined CDR sequences would be well within the scope of the skilled artisan's capabilities. The high percent identity ensures that only minor variation is possible, to provide suitable protection for the patentee. The skilled person would be capable of elucidating the key residues, and determining where changes are possible without affecting binding.
Examiner’s Response: The arguments found in the Reply of 03/02/2026 have been carefully considered but are not deemed persuasive.
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 a prima facie case are discussed below.
The nature of the invention
Claim 1 and all dependent claims, are drawn to fusion proteins capable of selectively binding Neu5Acα2-3Galβ1-3GalNAcα-R comprising a first binding domain comprising recited SEQ ID NO(s) for the VHCDRs and VLCDRs as well as CDR sequences with up to 10% mutations/variations, a second binding domain comprising specific SEQ ID NO(s) for the VHCDRs and VLCDRs as well as CDR sequences with up to 10% mutations/variations, and a human Fc domain (Fc). Further in claim 3, VH and VL domains of both binding domains comprise sequences with SEQ ID NO(s) as recited in the claim as well as sequences with up to 10% mutation/variations, which includes mutations in and around the VHCDRs and VLCDRs of the two binding domains of the fusion protein.
The breadth of the claims
The claim is broad in that it encompasses mutants, and/or variants with up to 10% mutations and/or variations in the CDRs, or with up to 10% mutations and/or variations of the VH and VL including the CDRs of the fusion protein that would retain the function of selectively binding Neu5Acα2-3Galβ1-3GalNAcα-R.
The claims are broad in that they are drawn to every possible mutant, and/or variant of the CDRs, VH or VL of the fusion protein with only at least 90% identity to the recited sequences that retains the function of being capable of selectively binding to Neu5Acα2-3Galβ1-3GalNAcα-R.
The amount of direction provided by the inventor/the existence of working examples
The specification at most discloses only one fusion protein species generated using humanized clone 1 and clone 2 (2G7.A8 mAb and 7F11.B9 mAb) (see Example 5 Pg 50-51). The specification also discloses Clone 3: 6H5.C10 Isotype Ig l k that can bind and form immune complexes with sialosylated glycosphingolipids and sialated glycoproteins, however there is no disclose that this clone was utilized in the generation of any fusion proteins.
The disclosure does not discuss, or demonstrate through working examples, any novel derivatives, mutants, and/or variants of the fusion protein generated from clone 1 and clone 2 (2G7.A8 mAb and 7F11.B9 mAb) that retain the instant claimed functionality.
The state of the art/the level of predictability in the art
The state of the art teaches that with regards to changes in the amino acid residues on binding domains, it is especially important to disclose which residues are permissive to mutation. As discussed in the Non-Final Office Action, even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982, see Abstract). Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
Not knowing and absent further experimentation, which modifications can retain antigen binding function and which cannot, even a single change of an encoded amino acid can unpredictably affect structure and function, leads to one having no predictability or expectation of success for the function of any given antibody modification. Such random experimentation to identify at a later time what structure or fragment or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
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 or otherwise envisage all possible clone 1 and clone 2 fusion protein derivatives that would retain the binding function to Neu5Acα2-3Galβ1-3GalNAcα-R. Therefore, in order to practice the invention as claimed, one of ordinary skill in the art would have to perform undue experimentation to create and function test all possible fusion protein derivatives, mutants, and/or variants for retention of functional activity that binds Neu5Acα2-3Galβ1-3GalNAcα-R.
Examiner confirms that Applicant is enabled for a fusion protein comprising in the first binding domain: vhCDR1, vhCDR2, vhCDR3 of SEQ ID NOs: 4, 5, 6 respectively, and vlCDR1, vlCDR2 and vlCDR3 of SEQ ID NOs: 7, 8 and 9 respectively; and comprising in the second binding domain: vhCDR1, vhCDR2, vhCDR3 of SEQ ID NOs: 10, 11, 12 respectively, and vlCDR1, vlCDR2 and vlCDR3 of SEQ ID NOs: 13, 14 and 15 respectively, and wherein each of the first and second binding domains are capable of selectively binding Neu5Acα2-3Galβ1-3GalNAcα-R. Applicant is also enabled for a fusion protein comprising VH1 that comprises SEQ ID NO:16, VL1 that comprises SEQ ID NO: 18, VH2 that comprises SEQ ID NO:18 and VL2 that comprises SEQ ID NO: 19.
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. This is because the art teaches that it is unpredictable whether or not CDR variants of known antibodies or binding domains will function as such, and the specification does not provide direction on which constructs below 100% identity have function, or do not have function, as claimed in order to perform the method as claimed. In other words, the specification does nothing to ameliorate these concerns over the breadth of the claims rejected above with respect to functional variants, therefore, one would be burdened with undue experimentation to make or use the products of instant claims as broadly as they are currently claimed.
Enablement can be met by amending claim 1 to recite the CDRs without any percentage identity variations. Similarly, the rejection of claim 3 can be overcome by amending the claim to recite the VH and VL domains without any percentage identity variations.
New Objections Necessitated by Amendments
Claim 1 is objected to because it appears to have three typographical errors. The claim should be amended to recite in the second to last line of the claim “…wherein each of the first and second binding domains is capable of selectively …..”. The suggested amendments are highlighted in bold.
Claim 14 is objected to because the phrase “L3 is a third linker and L4 is a fourth linker” in lines 7-8 would be better placed or moved to line 9 so that the claim recites in line 9: “iii) (VH1)-(L1)-(VL1)-(L3)-(Fc)-(L4)-(VH2)-(L2)-(VL2) where L3 is a third linker and L4 is a fourth linker; or”.
Conclusion
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 Yie-Chia Lee (Tonya) whose telephone number is (571)272-0123. The examiner can normally be reached Monday - Friday 7.30a - 3.30p Eastern Time Zone.
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/YIE-CHIA LEE (TONYA)/
Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
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