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 .
Status of the Claims
Claims 54,57-59,62-63,68-70 and 73-81 are currently pending in the Application with claims 62 and 73 currently withdrawn. Therefore claims 54,57-59,63,68-70 and 74-81 are examined on the merits below.
Response to Arguments - Claim Rejections - 35 USC § 112a-Written Description
In reply to previously applied rejection of claims 54, 57, 58, 59, 63, 68-70 and 81 under 35 USC section 112(a), written description Applicant traverses. Regarding the instant claim 54 and dependent claims, Applicant states that contrary to the rejection of record, the instant specification provides appropriate support for the variety of instantly claimed modifications to the IgA2 antibody. In support of the argument Applicant again directs one to specification [0108][0140] and further previously cited disparate locations of the specification as figure 12A, [0044][0034]. With respect to claim 54, as previously discussed, the paragraph 140 references the disclosure of Lohse (2016, of record) which is a reference which is utilized for art (103) rejections of the claims of interest. The disclosure of Lohse is further supported in the prior art rejections by the disclosure of Chuang to support an obviousness rejection of the claims. Therefore similar to previously presented rebuttal Applicant appears to utilize an obviousness-like analysis, utilizing disparate portions of the instant disclosure to arrive at the instantly claimed mutations to the N263 and N459 residues (N147 and N329 of SEQ ID NO: 11, respectively) mutations which are not explicitly, inherently or expressly disclosed. Applicant at best provides a schematic of IgA molecules with potential N- glycosylation sites designated and in separate portions of the disclosure such as [0140] describes that in general glycosylation may be reduced to result in “improved pharmacokinetics”.
Furthermore Applicant describes in claim 54 that the antibody is specifically “dimeric”, but further claims any mutation to the N263, or N459 residues of an IgA (1 or 2) molecule for purpose of not only providing a dimeric antibody, but also for the purposes of providing increased in vivo half-life of said engineered antibody relative to the half-life of wildtype IgA2 antibody.
Regarding the claim 63 and dependent claims the Applicant argues that the negative limitation presented as deletion of the entire tail-piece (18 amino acids) of an IgA CH3 region is properly supported by the as filed specification. Applicant relies on MPEP 2173.05.
However the specification does not disclose antibodies with and without a tailpiece as alternative embodiments. Thus the specification does not positively recite alternative elements as described in MPEP 2173. Applicant continues to cite figure 12 for support but all of the structures in figure 12 have a tailpiece. Figure 12D merely highlights the structure of the tailpiece, but is the same as 225IA2.0 antibody depicted in Figure 12A-C that also has the same tailpiece. The disclosure of a full length antibody in no way provides support for deleting specific structural features of the antibody. For example using the Applicant’s logic the disclosure of the hIGA2.0 structure would support deleting and/or modifying any region of the antibody since these are “positively recited”. For example deleting a hinge or a CH3 domain, or any individual amino acid/ amino acid sequence. This is clearly not the same as the situation described in MPEP 2173 as to what qualifies as a “positive recitation”.
Furthermore, similar to the arguments regarding the claim 54, Applicant appears to rely on a type of obviousness analysis to arrive at the conclusion that an artisan of ordinary skill would reasonably be aware that the Applicant was in possession of the claimed deletion mutants. The Federal Circuit has pointed out that, under United States law, a description that merely renders a claimed invention obvious may not sufficiently describe the invention for the purposes of the written description requirement of 35 U.S.C. 112. See Eli Lilly, 119 F.3d at 1567, 43 USPQ2d at 1405.
Response to Arguments - Claim Rejections - 35 USC § 112b indefinite
Applicant’s amendment to the instant claims have obviated the previously Applied rejection of record and therefore this basis of rejection is removed.
Response to Arguments - Claim Rejections - 35 USC § 103
In reply to previously applied rejections of record Applicant traverses with arguments significantly previously presented.
Regarding the claim 63 and dependent claims, in reply to previously applied rejection Applicant provides that because Atkin is concerned with an IgA1 tailpiece, and Applicant claims an IgA2 tailpiece region deletion there is no reasonable expectation that the claimed functional effects presented in the claim may be construed from the combination of references. Applicant essentially posits that IgA1 antibody and IgA2 antibody are distinct entity, and therefore structural homology is not translatable between molecules. However as indicated above, IgA1 and IgA2 molecules have identical amino acid composition of the tailpiece region including a N glycosylation site. Protein function is directly mediated by structural entities as such amino acid polymer. Identical structure can reasonably be expected to have similar function especially in the obviousness analysis presented. The deletion of a well characterized structural entity tailpiece region that is identical therefore would reasonably be expected to result in reduced glycosylation through abrogation of the conserved N glycosylation site, as well as abrogation of dimer formation as indicated by the combination of references above.
With regards to the rejection of claim 54, and dependent claims, Applicant similarly argues that one would not have a reasonable expectation of success to arrive at the claimed molecule with substitutions which “reduces glycosylation of said engineered antibody” when combining the cited references. Applicant subsequently argues that increased serum half-life is not assured through modification of the indicated residues which represent N linked glycosylation points in IgA1 when translated to IgA2 molecules. Applicant describes therefore that Chuang teaches away from making N263 mutation because of reduced (though not significant) reduction in serum half-life of N263 modified human IgA1 molecules introduced into mice.
Because as indicated in the previous applied rejection the claimed region of the human IgA1 molecule and human IgA2 isotype are structurally (amino acid sequence) identical at the indicated locations and represent N glycosylation sites one would reasonably expect that abrogation of said glycosylation sites in a IgA2 isotype would at least result in decreased glycosylation when compared to an unmodified IgA2 molecule. The disclosure of Chuang indicates that “further studies involving the manipulation of both amino acid residues as well as glycosylation will provide insights for designing Abs with optimal biologic activities”(p731, col2, paragraph 1). Furthermore the disclosure of Rifai indicates that the results of the experimentation performed “clearly indicate that the N-linked carbohydrate residues are important for clearance from blood by the ASGR” (p2180, col1, paragraph 2). As indicated above ASGR is the primary IgA removal mechanism in humans. Rifai further describes that the “results of their experiments suggest that the N-Linked carbohydrates in IgA “(including all the isotypes) “play an important role in the clearance from blood and uptake by the liver.” (p2172 paragraph 2). The disclosure of Rifai additionally clearly describes the O-linked glycosylation points found in the IgA1 hinge region as being not important for clearance of IgA1 for example by the ASGR. It would therefore be an obvious modification to reduce identical N-linked glycosylation sites present on an IgA (IgA1 or IgA2) molecule for purposes of increasing serum half-life of the modified molecule as described by Rifai and Chuang. The disclosure of Lohse further provides for targeted modification of the IgA2 isotype at the two additional N-linked glycosylation sites located in the molecule as described above for the purposes of increased serum half-life. One would do so with a reasonable though not absolute expectation of success.
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.
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 63, 68, 69, 70, 75, 77, 81 are rejected under 35 U.S.C. 103 as being unpatentable over Lohse (Cancer Res; 76(2) January 15, 2016)(published online first December 3, 2015)(of record) and further in view of Atkin (J Immunol 1996; 157:156-159)(of Record).
Claim 63 describes a monomeric IgA molecule which is primarily comprised of a deletion of the tailpiece region (18 amino acids) (Bur scheme residues 455-472). Additional mutations are introduced as for example the N337T mutation in claims 63, 68, 69. With respect to the claims 63, 68, 69 the disclosure of Lohse describes an engineered mutant of the IgA2 (m1) molecule which comprises a deletion of the terminal CY amino acid residues as important for dimerization and aggregation of the IgA molecules through complex formation and di-sulphide bond formation . As Lohse indicates (p406, col 2, paragraph 1) the removal of the N terminal CY from the tailpiece region of the IgA2 (m1) molecule results in significant abrogation of dimer formation and formation of predominantly monomeric forms of the engineered IgA Molecules. With regards to deletion of the entire tailpiece region of the IgG molecule the disclosure Lohse utilizes only the deletion of the N terminal CY residues. However the disclosure of Atkins as previously presented describes mutations to the N459 residue of IgA1 as well as entire deletion of the IgA1 tailpiece region as residues 455-472. The molecules are designated Pterm455 as well as NA459 (N459A) and were analyzed through SDS-PAGE for monomer and dimer and polymer formation (Figure 1) with the mutants analyzed showing reduced dimer formation under non-denaturing conditions. The disclosure additionally indicates that J chain is not associated with any of the tailpiece mutant that were analyzed (figure 2 , lanes 2-4). The disclosure thus indicates that both the tailpiece glycosylation site which may interact with the J chain which stabilizes the dimeric form of the IgA molecule (p159). It would be an obvious modification to the molecule of Lohse for example (IgA2) to remove entirely the C terminal “tailpiece region” as in Pterm455 (IgA1) as both IgA2 and IgA1 possess an identical amino acid structure in the tailpiece region (instant spec figure 12A for instance, Lohse figure 1) for the purposes of completely abrogating dimeric IgA formation as an alternative to simply removing the terminal CY amino acid residues. One would do so with a reasonable expectation of the same functional consequences as those which are presented by the disclosure of Atkins , and verified with respect to the terminal C residues by Lohse. As indicated below the disclosure of Lohse further recognizes that the removal of particular N-glycosylation residues as beneficial for the purposes of improved serum half-life in-vivo due to reduced asialo-glycoprotein receptor binding (ASGR) and improved pharmacokinetic properties (abstract). Thus the disclosure of Lohse provides clear evidence that the claimed mutations particularly at sites of N-glycosylation inherently lead to beneficial reduced removal of IgA molecules from serum “thereby increasing in vivo half-life of said engineered antibody relative to the half-life of wildtype IgA2 antibody” as described in the newly added limitation of claim 63.
The additional mutations that are indicated in the claims 68 and 69 (as N337T, mutating back to the IgA1 wild-type) , (Lohse, p405, paragraph 2) and C311S are indicated as providing superior thermal stability (P221R), formation of dimeric aggregates (C331S) (Results, p406) as well removal of glycosylation sites at N337(T) (Lohse, p404 col1) as a method of glycoengineering to prolong serum IgA half-life which may improve the immunotherapeutic potential of the IgA2m(1) derived antibody of the invention. In regards to the claims 70 and 77 the disclosure of Lohse for instance indicates that deletion of the terminal CY amino acid for example retains the ability of the tested molecule (IgA 2.0) to functionally bind to FcRalpha and elicit effective ADCC when target cells were exposed to GMCSF primed neutrophils (PMN, PolyMorphoNuclear cells which comprise neutrophils) (Table I and p411, column 1, paragraph 1). In regards to claim 75 and the requirement that the pharmaceutical composition would be provided in a unit dose form it would be obvious to provide a composition which is tested and created for the purpose of treating a patient with a disease in unit dose form for the purposes of convenient and reproducible end user medical professional administration.
Claims 54, 57, 58, 59, 74, 76, 78, 79, 80 are rejected under 35 U.S.C. 103 as being unpatentable over Lohse and further in view of Chuang and Rifai. The disclosure of Lohse makes obvious mutations as presented in the rejections of claim 63 and dependent claims as indicated above. The disclosure of Lohse does not particularly indicate that one might mutate the C terminal tailpiece N459 (Bur Scheme) in an IgA2(m)(1) molecule for example. However the disclosure of Chuang (J Immunol (1997) 158 (2): 724–732) and Rifai (J. Exp. Med. Volume 191, Number 12, June 19, 2000 2171–2181) describe variants of the IgA1 which are mutated at the locations of N263 (CH2) region and/or N459 (tailpiece,CH3) to remove N glycosylation sites (Chuang, results p725, figure 1). These residues and 100% homologous regions are identically found in the IgA2(m)(1) isoform of IgA2 molecules (instant spec, figure 12). The disclosure of Chuang indicates that mutation in either or both of the N-glycosylation acceptor sites had no effect on the formation of dimeric, polymeric or monomeric IgA as tested (p725)(figure 2C, 7-10) . The disclosure of Rifai further analyzed the mutation variants of the IgA1 and IgA2(m)(1) molecules and concluded that IgA2 clearance from the serum in humans is partially dependent on uptake by liver through recognition of glycosylated amino acid residues on the IgA molecule by the ASG receptor (ASGR) (p2180,paragraph 2). The disclosure indicates that increased levels of the glycosylation points on human IgA2 isotypes compared to IgA1 isotypes leads to increased clearance of IgA2 isotypes from the serum (p2180). Thus if one were interested in increasing serum half-life of IgA2 isotypes it would be obvious to remove the N glycosylation sites at N263 and/or N459 as are instantly claimed for the purposes of increasing serum half-life “in vivo” of the IgA2 molecule which in the case of therapeutic administration modalities would allow for fewer administrations of lower amounts of antibody as beneficial administration and production parameters. This therefore directly relates to the introduced limitation of claim 54 “thereby increasing in vivo half-life of said engineered antibody relative to the half-life of wildtype IgA2 antibody”. Based on the evidence provided Chuang and by both Lohse and Rifai it is obvious to conclude that in addition to continuing presence of a dimeric form of the IgA molecule (Chuang), the mutation of the claimed N263 and N459 moiety would lead to increased pendency time in the serum of subjects which may be injected with a “de-glycosylated” version of the IgA1 and/or IgA2 molecules at the indicated (2 or 4) N-glycosylation sites which reside outside of the hinge region, 2 of which are conserved between the IgA1 and IgA2 isotypes.
With regards to remaining claims 57, 58, 59, 74, 76, 78, 79, 80 the combined disclosure as indicated above makes obvious the claimed mutations in combination and/or alone as indicated by the disclosure of Lohse, Rifai and Chuang. It would be obvious to include the claimed products as a unit dose form for the purposes of convenient utilization in a clinical protocol. The disclosure of Lohse as indicated above describes that ADCC functions is retained in the IgA2 2.0 molecules further mutated IgA2(m)(1) N linked glycosylation site acceptors does not affect the binding of the produced IgA molecules to the FcRalpha and therefore ADCC effector functions.
Conclusion
Summary : No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
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/BRIAN HARTNETT/Examiner, Art Unit 1644
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671