Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of the Claims
1. Claims 1-44 are the original claims filed 3/10/2023. In the preliminary amendment of 10/11/2023, Claims 1, 5-6, 9, 11, 13, 16-19, 23, 25, 27-28, and 42 are amended and Claims 7, 8, 10, 14, 15, 20-22, 24, 29-4 1, 43, and 44 are canceled.
Claims 1-6, 9, 11-13, 16-19, 23, 25-28, and 42 are pending.
Election/Restrictions
2. Applicant’s election without traverse of Group I (claims 1-6, 9, 11-13, 16-19, 23, 25-27, and 42) in the reply filed on 4/14/2026 is acknowledged.
3. Claim 28 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/14/2026.
4. Claims 1-6, 9, 11-13, 16-19, 23, 25-27, and 42 are the claims under examination.
Priority
5. USAN 18025,792, filed 03/10/2023, is a National Stage entry of PCT/EP2021/ 075076, International Filing Date: 09/13/2021, PCT/EP2021/075076 Claims Priority from Provisional Application 63/078218, filed 09/14/2020.
Information Disclosure Statement
6. As of 6/7/2026, a total of one (1) IDS is filed: 10/11/2023. The corresponding initialed and dated 1449 is considered and of record.
Objections
Drawings
7. The drawing sheets for Figures 7, 8, 10, and 18 objected to because the use of the term Humira, which is a trade name or a mark used in commerce, has been noted in each figure. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
8. The disclosure is objected to because of the following informalities:
a) The use of the term Humira, Uniprot, Graphpad Prism, Remicade, SIMPONI, Cimzia, Enbrel, Amjevita, Cyltezo, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Objections
9. Claims 5-6, 16-19 are objected to because of the following informalities:
a) Claim 5 recites point mutations in reference to a protein comprising the VH or VL of an antibody. Technically, a point mutation occurs in a genome when a single base pair is added, deleted or substituted. While in the context of a protein, an amino acid can be mutated (inserted, deleted or added) as a consequence of a point mutation in the DNA. The limitation is improper absent a reference to a DNA level.
b) Claim 6 is unclear for reciting “one or more inserted or mutated amino acids.” The specification provides no definition for the meaning of an amino acid mutation. A mutation is presumed to encompass an insertion, deletion and/or substitution of an amino acid absent a showing to the contrary. Clarification is requested whether explicit and implicit inclusion of an “insertion” renders the species redundant.
c) Amend claims 16-18 to replace “represents” with “is”.
d) Amend claims 16 and 18 to recite “the
e) Amend claim 19(c) to recite “reduced” or “[[(]] lower [[)]]” but not both where the intended meaning is the same.
f) Claim 19 uses “__%” change and “__-fold” change for the respective activity being measured for each of elements (a)-(d). One nomenclature or the other is preferred but not both where the intended meaning is the same.
g) Amend claim 19(d) to replace “the anti-TNF antibody” with “the anti-TNFα antibody”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
10. Claims 9, 13, 16-18 and 42 are 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.
a) Claims 9 and 13(a)-(c) recite parenthetical text “(according to IMGT database and Eu numbering)” and “(according to IMGT database numbering)”, respectively. The parentheses containing the phrase renders the corresponding claim indefinite because it is unclear whether the limitation(s) with the parentheses are part of the claimed invention. See MPEP § 2173.05(d).
b) Claim 16-18 are indefinite because while the figures show locants on the structures, the linkages are not clear. For example, the linkage between the N-acetylglucosamines is labeled “4”, but the meaning is insufficient because the linkage could be any one or more of 1>4 or 3>4 or 4>4, etc. (assuming that the N-acetyl group is on the 2 position of the glucose and where that is NOT specified in the claims).
c) Claim 18 is generally narrative and indefinite, failing to conform with current U.S. practice. It appears to be a literal translation into English from a foreign document and is replete with grammatical and idiomatic errors. For example, the text does not comply with claim formatting under MPEP 608.01(i):
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d) Claim 18 is indefinite for concluding with two periods. See the separate arrows in the depiction. The POSA cannot reasonably ascertain the scope of the invention and whether or what limitations are omitted.
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e) Regarding claim 18, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
f) Claim 42 recites the limitation "the anti-TNFα antibody". There is insufficient antecedent basis for this limitation in the claim that depends from Claim 1. Claim 1 does not identify the target antigen for the monoclonal antibody.
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 the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Written Description
11. Claims 1-6, 9, 11-13, 16-19, 23, 25-27, and 42 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim interpretation
Claims 1 and 6, 9, 11-13, 16-19, 23, 25-27, and 42 are drawn to a monoclonal antibody comprising a higher amount of sialic acid in a Fab region of the monoclonal antibody as compared to an antibody found in human serum or a control monoclonal antibody produced by a Chinese hamster ovary (CHO) cell line.
Claim 2 is drawn to a monoclonal antibody comprising a higher amount of sialic acid in a Fab region and/or a higher amount of sialic acid in an Fe region of the monoclonal antibody as compared to an antibody found in human serum or a control monoclonal antibody produced by a Chinese hamster ovary (CHO) cell line.
Claim 3 is drawn to a monoclonal antibody comprising a higher amount of sialic acid in a Fab region and/or a higher amount of afucosylated glycan in an Fe region of the monoclonal antibody as compared to an antibody found in human serum or a control monoclonal antibody produced by a Chinese hamster ovary (CHO) cell line.
Claim 4 is drawn to monoclonal antibody comprising a higher amount of sialic acid in a Fab region and/or higher amount of GO glycan in an Fe region of the monoclonal antibody as compared to an antibody found in human serum or a control monoclonal antibody produced by a Chinese hamster ovary (CHO) cell line.
Scope of the claimed genus
There is no structure/function requirement for the claimed generic monoclonal antibodies.
The inventive monoclonal antibody is defined by a single de minimis feature, namely, that it has a higher amount of sialic acid in a Fab (Claims 1-2) and in an Fc region (Claim 2), or a higher amount of sialic acid in a Fab (Claim 3) and a higher amount of afucosylated glycan in an Fc region (Claim 3), or a higher amount of sialic acid in a Fab (Claim 4) and a higher amount of G0 glycan in an Fc region (Claim 4). The generic claims do not define how the monoclonal Ab is imbued with having a higher amount of sialic acid, afucosylated glycan, and/or G0 glycan. Claims 5-6 refer to amino acid mutation(s) or insertion(s) in the VH/VL domains of the monoclonal antibody of claim 1 without reference to the specific amino acid position(s) or residue(s) affected by increased sialylation. Claim 13 that depends from claims 1 and 12 identifies residues N84 and N86 for a anti- TNF-alpha antibody (a variant adalimumab). Otherwise, no insertions and mutations are identified in the generic claims.
The generic claims do not define how the sialic acid, afucosylated glycan, and/or G0 glycan are within a structure context for the Fab and/or Fc. Claims 16-18 in depending from Claim 1 are for the sialylated Fab of claim 1, but not necessarily those sialylations for the Fab of any one of Claims 2-4. Claim 16-18 are addressed for their indefiniteness above.
Each of generic claims 1-4 is drawn to a monoclonal antibody where the control antibodies, i.e., any polyclonal antibody found in human serum or any control monoclonal antibody produced by a CHO cell line, dictates how that specific monoclonal antibody is defined. The control monoclonal antibody is not identified as being a wild-type to the inventive monoclonal antibody.
The genus of monoclonal antibodies is beyond those taught in the specification. Because applicant seeks patent protection for all such monoclonal antibodies, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
State of the Art for Glycosylated Antibodies
The prior art teaches that antibodies undergo extensive glycosylation by glycosylating enzymes in the ER and the Golgi apparatus of the host cell (Werner et al. Acta Paediatr. Suppl. 96(455):17-22 (2007)).
Wright et al (Springer Semin Immunopathology ,15 :259-273 (1993)), the glycosylation of the VH chain “contributes to alterations in protein stability that Iead to the formation of immune complexes or tissue deposition'' and Wright et al further caution that ''disruption in the regulation of glycosylation can Iead to the expression of altered carbohydrate structure (such as galactosyl sugars) with a resulting glycoprotein exhibit properties (such as a tendency towards aggregation) that contribute to disease'' (page 270, second to Iast paragraph). Moreover, Wright. et al teach while N-linked glycosylation is a wide spread post translational modification, occurring among mammalian, yeast, insect and plant cells, ''the processing steps in the Golgi apparatus vary among cell types''. (Page 259, second paragraph). Wright documents that plant cells use xylose, mammalian cells use sialic acid, and yeast add many mannose monomers than mammalian cells. Also insect cells do not appear to process the carbohydrates beyond the Man3 GLC Nac2 step. Accordingly, one skilled in the art would reasonably conclude that the tertiary structure of glycosylated antibodies, if actually glycosylated, which are encompassed by the broadly written claims would differ, based upon the teachings of Wright et al.
Further, Wright et al specifically teach that ''the position of the carbohydrate addition appears to influence the structure of the added carbohydrate'' (page 269, first full paragraph) and that ''glycosylation can induce structural abnormalities in the light chain that Iead to tissue deposition'' (page 266-267, bridging paragraph). Further, Wright et al go on to teach that ''many Vh3 genes ... contain potential N-linked glycosylation sites as ASN 72, in FR3, although it has not yet been determined whether any of these sites are in fact glycosylated''.
Finally, Wright et al teach that the sugars may fill “pockets'' within the immunoglobulin, thus one of ordinary skill in the art would reasonably conclude that addition of carbohydrates to an antibody would alter the tertiary structure as evidenced from Delente (Trends in Biotechnology 3, Ietters to editor, No.9, (1985)) which teaches each glycosylated protein must be evaluated individually to determine the importance of glycosylation to its function and stability. Thus, Wright et al teach the unpredictability of adding a glycosylation site to an antibody molecule, specifically that some additions result in protein aggregation, that the position of the addition is important for determining whether the glycosylation site is in fact recognized by the cell, and once glycosylated, whether the antibody is more or less stable and binds the corresponding antigen in the unaltered form. One skilled in the art would also reasonably conclude from Wright et al that glycosylation in the CH1 or constant K (CK) region could have similar structural effects as those in the Iight chain mentioned above.
As evidenced by Olden et al (Biochem et Biophys Acta 650:209-232 (1982)), carbohydrate structures are a form of sorting signals used by the cells and that O-linked glycosylation differ from N-linked glycosylation due to the sugars which are added to each type during protein processing. O-linked carbohydrates use gaINAC while N-Iinked carbohydrates use GIcNAC (see page 225, second column, first paragraph). Olden teaches that O-linked carbohydrates differ in tertiary structure from N-linked carbohydrates and therefore, one skilled in the art would reasonably conclude that antibodies possessing O-linked sugars would also differ in their tertiary structure from those antibodies expressing N-linked sugars.
Since the state of the art of suggests that the effects of antibody glycosylation contribute to not only processing and secretion of antibodies, but as evidenced by Wright et al, Delente, and Olden et al, that glycosylation contributes to antibody stability/function, it is critical that the antibody binding activity is not reduced.
Whether and the extent to which any antibody is glycosylated is an unpredictable event, and whether the variable domain is glycosylated is even further unpredictable. Sato et al. (Hum. Antibodies Hybridomas 7:175-183 (1996)) teaches on p. 176, Col. 1:
“Numbers of antibodies possess a potential N-glycosylation site (Asn.X-Thr/Ser) in their variable regions. Indeed, up to 25% of human IgG myeloma proteins were shown to have carbohydrates in these regions. Although the roles of carbohydrates in antibody variable regions are still unclear, they may influence solubilization of antibodies, localization and distant-modification of CDR conformations, interaction of heavy and light chains, and antigen-binding.”
The POSA could reasonably conclude that introducing myriad amino acid insertions and/or mutations effecting the sialylation status of an antibody much less within the VH/VL domains of Fc regions would not effect, for example, glycosylation sites required by the antibody molecule to be expressed in a soluble form from a eukaryotic host and bind its antigen.
Are the disclosed species representative of the claimed genus?
The disclosure in the specification is for those limited data shown in the figures for the K84N-D86N (Fab) mutations and conserved N-297 (Fc):
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It is asserted that the disclosed species are not representative of the claimed genus because the claims encompass all amino acid insertions and/or mutations for Fab and Fc regions of a genus of any monoclonal antibody.
Has Applicant provided a common structure sufficient to visualize the genus?
Applicant has not provided a common structure sufficient to visualize the genus of all possible functional variants of a sialylated Fab and/or Fc region.
It is asserted that neither the specification nor the state of art at the time of filing disclosed structural features common to the members of the genus for reliably assigning different antibody structures based on limited data for mutation-mediated sialylation of antibody clones, which would support the premise that the inventors possessed the full scope of the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
12. Claims 1, 5-6, 9, 11-13, 16-19, 23, 25-27, and 42 is/are rejected under 35 U.S.C. 103 as being obvious over Mally et al (WO 2019/234021 A1; Published 12/12/2019 (IDS 10/11/2023) in view of van de BovenKamp et al (IDS 10/11/2023; “vdB”).
The applied reference (“Mally”) has a common assignee and common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
The interpretation of the claims is established on the record.
AS regards claims 1, 11-12, Mally teaches a Mab Fab with higher amounts of sialylation than a control in claims
12. An anti-TNFa antibody produced by the method of claim 10 or 11.
13. The anti-TNFa antibody of claim 12 wherein the anti-TNFa antibody has maximal a-2,6 sialylation.
14. The anti-TNFa antibody of claim 13 wherein the“maximal” a-2,6 sialylation is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of N-glycans comprising at least one sialic acid residue per N-glycan or comprising at least two sialic acid residues per N-glycan.
15. The anti-TNFa antibody of claim 13 wherein at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of N-glycosylation consensus sequences are glycosylated.
16. The anti-TNFa antibody of claim 12 wherein at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of N-glycans are not mannose 5 (Man5) glycan or mannose 6 (Man6) glycan.
AS regards clam 9, Mally teaches an afucosylated glycan at 8.1 Example 1A: Maximally sialylated adalimumab is produced by an in vitro N-glycan remodeling of commercial HUMIRA
[00359] To achieve the target effects described above, highly sialylated and entirely defucosylated adalimumab with 80% of the N-glycans containing at least one sialic acid residue per N-glycan, along with the appropriate critical quality attributes (CQA) suitable for the preclinical assays, is required. To our knowledge, only the in vivo production using the Lt system is capable of doing so. However, multiple production strategies are employed which approach the target product specifications (Figures 1 and 2).
[00360] First, maximally sialylated adalimumab is produced by an in vitro N-glycan remodeling of commercial HUMIRA (Figure 1, left panel). The methods to perform such modification reaction are established and described and can be applied by scientists skilled in the art based on the instruction manual. Such product will retain the degree of fucosylation intrinsic to the HUMIRA product, which is > 90%, thus not fulfilling the condition of being completely defucosylated. Such a-2,6 sialylated adalimumab was synthesized by in vitro glyco-engineering as described above, demonstrating a maximal Fc a-2,6 sialylation (of 80% of N-glycans contain at least one sialic acid residues per N-glycan whereby 60% is biantennary sialylated (G2FS2) and 20% is mono-sialylated (G2FS1), Figure 4). The in vitro reaction used recombinant
glycosyltransferases to re-model the N-glycan profile of HUMIRA, the CHO produced adalimumab commercial product to be used for the proposed preclinical assays.
AS regards claim 16, Mally teaches identical sialylated structures as alpha 2,6
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As regards claim 17, Mally teaches identical sialylated structures but as alpha 2,3 at [0023], [00267].
AS regards claim 18, Mally teaches [00144] Table 1 lists the glycan names and abbreviations used herein. Table 1: Glycan names.
As regards claim 19(a), Mally teaches at 36. The anti-TNFa antibody of any one of claims 12 to 17, wherein the anti-TNFa antibody has an antibody-dependent cell mediated cytotoxicity (ADCC) activity that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7- fold, 8-fold, 9-fold, lO-fold, l2-fold, l5-fold, l8-fold, 20-fold, 25-fold, or 30-fold higher than that of the same anti-TNFa antibody having a different glycosylation profile.
AS regards claims 19(b), Mally teaches at 40. The anti-TNFa antibody of any one of claims 12 to 17, wherein the anti-TNFa antibody has an anti-inflammatory activity that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, lO-fold, 12- fold, 15-fold, 18-fold, 20-fold, 25-fold, or 30-fold higher than that of the same anti-TNFa antibody having a different glycosylation profile.
AS regards Claim 19(c), Mally teaches reduced immunogenicity at [00174] [00178] [00179].
AS regards Claim 19(d), Mally teaches effecting M2 macrophage activity at [00423].
AS regards Claims 23 and 25-26, Mally teaches at Claim 1 Leishmania host cell comprising: a. a recombinant nucleic acid encoding an anti-TNFa antibody heavy chain (and optionally a recombinant nucleic acid encoding an anti-TNFa antibody light chain and in subsequent claim 2 the glycan structures in instant claim 16 discussed herein.
AS regards claim 27, Mally teaches pharmaceutical compositions at [00320], [00303].
AS regards claim 42, Mally claims at 33. A single dosage form of an anti-TNFa antibody of any one of claims 12 to 17, wherein the single dosage form consists of about 2 mg, about 5 mg, about 7 mg, about 10 mg, about 12 mg, about 15 mg, about 18 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or about 80 mg of the anti-TNFa antibody.
The claims are prima facie obvious over Mally in view of van de BovenKamp (“vdB”) because vdB teaches an anti-TNF alpha antibody monoclonal antibody comprising a higher amount of sialic acid in the Fab region compared to human serum or a CHO-produced control monoclonal antibody.
AS regards Claims 5-6, vdB teaches mutations in the variable domain of a VH or VL or insertions or mutations in the VH and/or VL.
AS regards Claim 13, vdB teaches positions 86 and 84 of adalimumab.
“vdB” teaches the introduction of a glycosylation site into a Fab region of a monoclonal antibody, adalimumab (anti-TNF alpha), at predicted progenitor positions. Of the 8 positions analyzed in the Fab antibody model, 7 positions are glycosylated including positions 86 and 84 in the Fab (or light can heavy chains), respectively.
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The glycans include sialic acid, galactose, and N-acetyl-glucosamine. Figure 3 shows the effect of these sites on affinity and the ability of anti-idiotype antibodies (ADAs from patients) to bind the adalimumab variants. Accordingly, “vdB” teaches increased sialic acid for Fab antibodies in methods that do not involve CHO cells. Instead, the methods involve analyzing B cell repertoires by next generation sequencing as a result of naturally occurring N-glycosylation sites in the germline sequences of variable domain genes from antigen specific antibody responses.
The references alone and in combination provide the motivation and a reasonable assurance of success by teaching methods for production and the resulting product of a monoclonal antibody with specific glycosylation profile that results in improved efficacy. The impact of the structural characteristics and homogeneity on efficacy is accessed with a selection of in vitro, in vivo and ex vivo mechanistic assays, in particular by measuring the ability to reduce the amount of anti-drug antibodies cause by the monoclonal antibody, and secondly by the ability to induce other effects as known in the art for the particular antibody. Such glycan modifications will improve current treatments and allow a better quality of life for patients.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Rejections Maintained
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
13. The rejection of Claim(s) 1, 5-6, 12-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over van de BovenKamp et al (IDS 10/11/2023; “vdB”) is maintained.
Applicants have not responded by a traversal on the record to the outstanding grounds for rejection set forth in the Office Action of 1/16/2026. New claims 5-6 are added to the rejection.
The rejection is maintained as follows:
Claim interpretation
Most generic claim 1 is drawn any monoclonal antibody comprising a higher amount of sialic acid in the Fab region compared to human serum or a CHO-produced control monoclonal antibody.
Claims 5-6 are drawn to mutations in the variable domain of a VH or VL or insertions or mutations in the VH and/or VL.
Claim 12 is drawn to the antibody being adalimumab.
Claim 13 is drawn to positions 86 and 84 of adalimumab.
The claims are prima facie obvious over van de BovenKamp (“vdB”).
“vdB” teaches the introduction of a glycosylation site into a Fab region of a monoclonal antibody, adalimumab (anti-TNF alpha), at predicted progenitor positions. Of the 8 positions analyzed in the Fab antibody model, 7 positions are glycosylated including positions 86 and 84 in the Fab (or light can heavy chains), respectively.
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The glycans include sialic acid, galactose, and N-acetyl-glucosamine. Figure 3 shows the effect of these sites on affinity and the ability of anti-idiotype antibodies (ADAs from patients) to bind the adalimumab variants. Accordingly, “vdB” teaches increased sialic acid for Fab antibodies in methods that do not involve CHO cells. Instead, the methods involve analyzing B cell repertoires by next generation sequencing as a result of naturally occurring N-glycosylation sites in the germline sequences of variable domain genes from antigen specific antibody responses.
The rejection is maintained.
Conclusion
14. No claims are allowed.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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