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 .
Claim Status
Claims 1-18 were previously pending.
A non-final rejection office action was mailed 29 December 2025.
In response to that office action, Applicant filed an Amendment/Request for Reconsideration whereby Applicant amended claims 1-4, 10-11, and 13. No claims were cancelled or added.
Therefore, claims 1-18 remain pending and currently under examination.
Priority
Examiner acknowledges Applicant’s claim to the following priority:
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Withdrawn Claim Rejections
I. The previously held rejection of claims 1 and 2 under 35 USC 101 as being directed to a natural phenomenon without significantly more is hereby withdrawn in view of the amendment to claim 1. As presently amended, claim 1 affirmatively requires the physical step of extracellularly mixing the dimeric and monomeric IgA antibodies for the purposes of producing a trimeric or tetrameric IgA antibody. Considering this claim as a whole, the claimed manipulation constitutes a practical laboratory application rather than merely the existence of naturally occurring IgA association. Accordingly, the previous rejection of claims 1 and 2 under 35 USC 101 is withdrawn.
II. The previously held rejection of claims 1, 2, 7,10, and 11 under 35 USC 102(a)(1)/102(a)(2) as being anticipated by Saito (US 2017/0340732) is hereby withdrawn in view of the amendment to claim 1. The withdrawal of this rejection should not be interpreted as a determination that the amended subject matter is patentable. The amended claims are rejected under 35 USC 103 for the reasons set forth below.
III. The previously held rejections of claims 3-4 under 35 USC 103 as being unpatentable over Saito in further view of Keyt (US 2016/0368971) is hereby withdrawn in view of the amendment to claim 1. The withdrawal of this rejection should not be interpreted as a determination that the amended subject matter is patentable. The amended claims are rejected under 35 USC 103 for the reasons set forth below.
IV. The previously held rejections of claim 8 under 35 USC 103 as being unpatentable over Saito in further view of Lilie (“Influence of protein disulfide isomerase (PDI) on antibody folding in vitro”) is hereby withdrawn in view of the amendment to claim 1. The withdrawal of this rejection should not be interpreted as a determination that the amended subject matter is patentable. The amended claims are rejected under 35 USC 103 for the reasons set forth below.
New Claim Rejections
Applicant’s amendment to claim 1 newly requires that the dimeric IgA antibody and monomeric IgA antibody be mixed extracellularly. This limitation was not present in the claims previously examined and necessitates reliance upon additional prior art addressing the extracellular manipulation and oligomerization of separately produced IgA antibodies.
Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 7, 10, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Saito (previously cited) in further view of Lombana (“Production, characterization, and in vivo half-life extension of polymeric IgA molecules in mice,” published 09 June 2019).
Saito teaches methods for producing polymeric IgA antibodies, including trimeric and tetrameric IgA species ([0104]). Saito teaches recombinant production of IgA in mammalian cells by expression of IgA heavy chain, light chain, J chain, and, in certain embodiments, secretory component (claim 6).
Regarding instant claim 1, Saito discloses a polymeric IgA-type recombinant antibody is a mixture of monomeric, dimeric, trimeric, and tetrameric antibodies ([0106]). Experimental Example 4 described the production of a polymeric IgA1-type antibody ([0224]-[0236]) and Experimental Example 21 provides data for the mass spectrometer analysis of this antibody ([0355]-[0364]). Data shows the tetrameric IgAm2 contains a mixture of monomers and dimers ([0361]-[0362], Table 8).
Regarding instant claim 2, Saito discloses the addition of a secretory component to the mixture to produce the antibodies in Experimental Example 4 ([0225]).
Regarding instant claim 7, Saito discloses the secretory component is mutated (p. 35, SEQ ID NO: 31).
Regarding instant claims 10 and 11, Saito discloses the IgA1 and IgA2 antibodies were separated based on molecular size using size exclusion chromatography ([0283]).
While Saito does not expressly teach that a previously formed dimeric IgA antibody and a previously formed monomeric IgA antibody are thereafter mixed extracellularly, this limitation is made obvious in view of Lombana.
Lombana teaches recombinant production, isolation, purification, and characterization of monomeric, dimeric, and polymeric IgA species (abstract). Lombana teaches the mechanism by which IgA oligomers form (p. 1123). Specifically, Lombana teaches each IgA monomer contains two heavy chain tailpieces, and following formation of a J chain-containing IgA dimer, two C-terminal cysteine residues remain available for further intermolecular linkage (p. 1122). Lombana expressly teaches that these remaining cysteine residues can participate in the linkage of additional IgA monomer units and recognizes the resulting higher order IgA species, including trimers, tetramers, and pentamers (p. 1122).
Lombana further teaches purification and handling of the individual IgA oligomeric species outside of the producing cell, including isolation of monomeric and dimeric IgA preparations by chromatographic techniques (pp. 1124-1126).
Thus, the prior art teaches: 1) formation of trimeric and tetrameric polymeric IgA antibodies as in Saito; and 2) that separately obtainable IgA monomers and dimers possess the structural groups responsible for further IgA oligomerization and may be isolated and manipulated in vitro, as taught by Lombana.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to modify Saito’s production of higher order IgA polymers with Lombana’s teaching that a dimer retains available cysteine residues capable of linkage to additional IgA monomer units. This modification would result in bringing an isolated dimeric IgA preparation into contact with an isolated monomeric IgA preparation under extracellular conditions in order to permit formation of higher order IgA oligomers.
A person of ordinary skill would have been motivated to make this modification because extracellular combination of separately prepared IgA species would permit control over the identity and relative amounts of IgA components without requiring all of the antibody components to be simultaneously expressed in the same cell. Such manipulation would have facilitated isolation, characterization, and control of the desired oligomeric species as emphasized by Lombana.
This modification employs the known chemical functionality with which the prior art understood IgA monomers to become covalently incorporated into higher order IgA oligomers. Therefore, the skilled artisan would have had a reasonable expectation that contacting a dimeric IgA with a monomeric IgA under suitable conditions would produce higher order IgA species, including trimeric and/or tetrameric IgA.
Accordingly, claims 1, 2, 7, 10, and 11 would have been obvious over Saito in view of Lombana.
Claims 3 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Saito (previously cited) and Lombana (previously cited) as applied to claims 1, 2, 7, 10, and 11 above, and in further view of Keyt (previously cited).
The teachings of Saito and Lombana are discussed above. While the combination of references does not explicitly disclose the limitations of instant claims 3-4, these components of the currently claimed invention are made obvious in view of Keyt.
Keyt discloses IgA multi-specific binding molecules, methods for their preparation, and use (abstract). In addition, Keyt discloses bi- and multi-specific IgA antibodies have great potential in the treatment of respiratory virus infections, various bacterial infections of the gastrointestinal tract, and immunology of cancer ([0010]).
Regarding instant claim 3, Keyt discloses the methods of the present invention will result in a composition comprising a bispecific IgA antibody possibly in combination with monomers, dimers, trimers, and/or tetramers of the bispecific binding unit ([0128]). Furthermore, Keyt discloses that in some embodiments of the bispecific binding molecule, each of the binding units is monospecific (AA, BB), each binding to a different binding target (A and B, respectively) ([0012]). Keyt further discloses the bi-specific antibody of the invention has at least two antigen-binding sites ([0007]).
Regarding instant claim 4, Keyt discloses that in some embodiments of the bispecific binding molecule, each binding unit is bispecific with different binding specificities ([0104]).
Accordingly, the combination of Saito, Lombana, and Keyt disclose the limitations of instant claims 3-4. Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to use the combined teachings of the references to arrive at the claimed invention. It would have been obvious to employ, in the extracellular combination taught by Saito and Lombana, a dimeric IgA directed to a first antigen and a monomeric IgA directed to a second antigen, as taught by Keyt, in order to obtain a higher order IgA possessing the antigen-binding functions of the constituent IgA units.
The motivation to do so is expressly provided by Keyt: multispecific IgA permits a single IgA molecule to recognize different epitopes or targets and thereby provides increased functional versatility, avidity, and/or therapeutic activity. Because antigen specificity resides in the antibody variable/Fab regions, while IgA oligomerization occurs through the constant region, tailpiece, or J chain-associated structures, one of ordinary skill would have understood that selecting different variable region specificities would not eliminate the known ability of the IgA constant regions to participate in oligomerization.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Saito (previously cited) and Lombana (previously cited) as applied to claims 1, 2, 7, 10, and 11 above, and in further view of Lilie (previously cited).
The teachings of Saito and Lombana are discussed above. Though the combination of references does not explicitly disclose use of a molecular chaperone protein, a disulfide bond isomerase, oxidized glutathione, and reduced glutathione as required by instant claim 8, these components of the currently claimed invention are made obvious in view of Lilie.
Lilie teaches eukaryotic protein disulfide isomerase (PDI) is known to participate in the disulfide bond formation of immunoglobulins in vivo (abstract). Lilie further teaches PDI catalyzes the assembly of IgM and IgA in vitro (p. 14290). Finally, Lilie teaches PDI influences the yield of reactivation enormously and in the presence of PDI, formation of the correct disulfide bonds is possible at higher oxidizing conditions compared to the spontaneous reaction (abstract). Therefore, Lilie teaches the necessity of PDI in antibody formation especially in the early phases of structure formation (p. 14296).
Lombana teaches that higher order IgA formation proceeds through available cysteine residues and intermolecular disulfide linkage.
Therefore, it would have been obvious, before the effective filing date of the claimed invention, to use the combined teachings of the references to arrive at the claimed invention. It would have been obvious to employ a known disulfide bond isomerization/redox system as taught by Lilie when performing the extracellular IgA association discussed above in Saito and Lombana, because the desired IgA oligomerization depends upon the formation and/or rearrangement of intermolecular disulfide bonds. A person of ordinary skill would have reason to employ PDI and/or known glutathione redox reagents to facilitate appropriate cysteine oxidation and disulfide bond formation under in vitro conditions.
Accordingly, claim 8 is unpatentable over Saito and Lombana in view of Lilie.
Maintained Claim Rejections
Claims 12-13 and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Saito (previously cited) in further view of Keyt (previously cited).
The disclosures in Saito are discussed above. Though Saito does not explicitly disclose the limitations of instant claims 12-13 and 17-18, these components of the currently claimed invention are made obvious in view of Keyt.
Keyt discloses IgA multi-specific binding molecules, methods for their preparation, and use (abstract). In addition, Keyt discloses bi- and multi-specific IgA antibodies have great potential in the treatment of respiratory virus infections, various bacterial infections of the gastrointestinal tract, and immunology of cancer ([0010]).
Regarding instant claim 12, Keyt discloses the methods of the present invention will result in a composition comprising a bispecific IgA antibody possibly in combination with monomers, dimers, trimers, and/or tetramers of the bispecific binding unit ([0128]). Furthermore, Keyt discloses that in some embodiments of the bispecific binding molecule, each of the binding units is monospecific (AA, BB), each binding to a different binding target (A and B, respectively) ([0012]). Keyt further discloses the bi-specific antibody of the invention has at least two antigen-binding sites ([0007]).
Regarding instant claim 13, Keyt discloses the bi-specific antibody can further comprise a secretory component ([0054], [0059]).
Regarding instant claim 17, Keyt discloses the bi-specific antibody can further comprise a secretory component ([0054], [0059]). While Keyt does not explicitly disclose the secretory component can be a wild type or mutant, Saito identifies the secretory component by sequence identifier and indicates the secretory component suitable for use with polymeric IgA antibodies can be a mutant secretory component (p. 35, SEQ ID NO: 31).
Regarding instant claim 18, Keyt discloses the bi-specific antibody can be formulated into a pharmaceutical composition ([0155]-[0157]).
A combination of Saito and Keyt disclose the limitations of instant claims 12-13 and 17-18. Therefore, it would have been obvious, before the effective filing date of the claimed invention, to use the combined teachings of the references to arrive at the claimed invention. Both Keyt and Saito disclose a method of making IgA antibodies. Keyt further discloses a method of making bi-specific IgA antibodies and their potential in the treatment of respiratory virus infections, various bacterial infections of the gastrointestinal tract, and immunology of cancer ([0010]). Keyt not only discloses the limitations of instant claims 12-13 and 17-18, but also provides motivation to manipulate the base IgA antibody taught by Saito to include bi-specific properties and antigen-binding configurations. Therefore, one of ordinary skill in the art could improve upon the base method and composition disclosed by Saito with what is taught in Keyt and arrive at what is currently claimed in instant claims 12-13 and 17-18 with reasonable expectation of success.
Claim Objections
Claims 5-6, 9, and 14-16 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Prior art, including the references Saito and Keyt, do not explicitly disclose which component (monomer or dimer) of the trimeric or tetrameric antibody contains which antigen binding site nor does either reference contain motivation for this limitation. Furthermore, neither reference explicitly teaches separately producing the recombinant dimeric and monomeric IgA antibody in separate cells. In fact, Saito teaches against this limitation as the scope of Saito’s invention involves producing antibodies in a single cell, rather than multiple and different cells (see, for example, abstract and [0134]: “the present inventors have first succeeded in unexpectedly producing a polymeric IgA-type antibody by coexpressing a secretory component protein in a single cell together with an IgA-type antibody heavy-chain protein, an antibody light-chain protein, and an antibody J-chain protein”).
Response to Applicant’s Arguments
Applicant’s arguments, filed 29 June 2026, have been fully considered but are not persuasive except to the extent specifically indicated above.
Arguments Concerning Anticipation by Saito
Applicant argues Saito does not disclose extracellularly mixing a dimeric IgA antibody and a monomeric IgA antibody because Saito instead teaches coexpression of IgA heavy chain, light chain, J chain, and secretory component proteins within a single cell.
The examiner agrees that Saito does not expressly disclose the newly added extracellular mixing limitation. Accordingly, the rejection under 35 USC 102 based upon Saito alone has been withdrawn.
However, Applicant’s amendment necessitated further consideration of the prior art concerning the known extracellular/in vitro handling and oligomerization properties of separately produced IgA species. As discussed above, Lombana teaches separately obtainable and purified monomeric and dimeric IgA species and expressly teaches the dimer retains available cysteine residues through which additional IgA monomers can become linked to produce higher order IgA oligomers such as trimeric or tetrameric IgA antibodies.
Thus, although Saito alone does not anticipate amended claim 1, the limitations would have been obvious over Saito in view of Lombana.
Arguments Concerning the Combination of Saito and Keyt
Applicant argues Saito does not disclose extracellularly mixing a dimeric IgA antibody and a monomeric IgA antibody because Saito instead teaches coexpression of IgA heavy chain, light chain, J chain, and secretory component proteins within a single cell.
This argument has been considered. The rejection of claims 3 and 4 is no longer premised solely upon Saito and Keyt. Lombana is additionally relied upon for the teachings concerning separately produced IgA species and high order oligomerization as discussed above.
Applicant further argues Keyt produces bispecific antibodies by engineering DNA constructs and transfecting the constructs into cells and therefore, does not teach the claimed extracellular method.
This argument is not persuasive because Keyt is not relied upon for the extracellular mixing limitation. The test for obviousness does not require that all limitations be expressly disclosed in a single reference, nor does it require bodily incorporation of Keyt’s entire production process into Saito’s production process. Rather, the inquiry stands on whether the combined teachings would have suggested to one of ordinary skill in the art.
One of ordinary skill would have understood from Keyt that the variable regions of IgA units can be selected or engineered to provide different antigen-binding specificities. One of ordinary skill would have also understood from the IgA oligomerization art that polymerization is mediated through portions of the IgA molecule distinct from the antigen-binding variable regions. Thus, using different IgA components in the known IgA oligomerization system would have predictably retained the antigen specificities of the constituent IgA units while providing a higher order, multispecific IgA.
Applicant additionally argues that even if Saito were modified by Keyt’s teachings of bispecificity, the resulting antibodies would contain a random mixture of IgA chains and therefore, would not necessarily possess the claimed bispecificity.
This argument is not persuasive. The rejection does not propose indiscriminately introducing unrelated expression vectors into a single Saito cell and relying upon random association. Keyt expressly teaches IgA molecules containing different antigen binding specificities that are controlled. The obvious modification would be to employ IgA components having the respective known specificities in the oligomerization process. When an IgA dimer, having a first antigen-binding specificity, is combined with an IgA monomer, having a second antigen-binding specificity, the units oligomerize and the resulting oligomer contains the same antigen binding regions carried by those constituent IgA units. The resulting oligomer possesses, at the very least, the first and second antigen binding specificities of the separate components. Moreover, claim 3 does not require any particular orientation of the IgA units, any particular interchain architecture beyond the recited dimer/monomer relationship, or any particular proportion of molecules possessing the claimed bispecificity.
Accordingly, Applicant’s arguments do not overcome the rejection.
Conclusion
Claims 1-4, 7-8, 10-13, and 17-18 are rejected. Claims 5, 6, 9, and 14-16 are objected to. No claim is allowed.
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.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Julia A. Rossi whose telephone number is (571)272-0138. The examiner can normally be reached M-Th 7:30-5:30 (MST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A. Wax can be reached at (571)272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JULIA A. ROSSI/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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