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 .
Claims 1-20 are pending and under examination.
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.
Claim(s) 1-5 and 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over Lau et al. (20150231212, cited on an IDS) in view of Jones et al. (Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):7207-12, cited on an IDS) and Henry et al. (10870837, cited herewith) as evidenced by Washburn et al. (Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):E1297-306 and supplemental pages 1-5, cited herewith).
Lau teaches systemic ST6Gal-1 levels are decreased during acute inflammation (see Example 1); however, further according to Lau provision of recombinant ST6Gal-1 into the systemic circulation can attenuate inflammatory reactions, e.g., airway inflammation (see para 0013 and Fig. 8).
The release of intracellular ST6Gal-1 into the systemic circulation via intracellular proteolysis is described at para 0037 of Lau (emphasis added):
“…In the native form, ST6Gal-1 is localized in the Golgi, where it participates in the assembly of sialyl-glycoconjugates transiting the secretory apparatus. The intact catalytic domain can be proteolytically liberated and released into systemic circulation as the soluble ST6Gal-1 form. Therefore, ST6Gal-1 can be divided into two conceptual categories: The ‘cell-restricted’ ST6Gal-1 that remains within the cells that produced them, and the ‘circulatory’, or ‘soluble’, ST6Gal-1 that has been released into systemic circulation. Circulatory ST6Gal-1 originates predominantly from the liver; specific inactivation of the liver-restricted promoter (P1) of the ST6Gal-1 gene results in depressed systemic ST6Gal-1 levels.” At para 42 Lau provides the sequence of the circulatory /systemic form of the 380aa protein “rST6Gal-1.”
At claim 4 Lau teaches the treatment of an allergic reaction by administering recombinant α2,6-sialyltransferase (rST6Gal-1):
“A method for prophylaxis and/or therapy of inflammation or an allergic reaction in an individual in need thereof, the method comprising administering to the individual a composition comprising an effective amount of recombinant α2,6-sialyltransferase (rST6Gal-1), wherein the administration results in a reduction or inhibition of inflammation or an allergic reaction in the individual, wherein the allergic reaction is a Type I hypersensitivity allergic reaction, and wherein the administering comprises an intravenous injection of the composition comprising the rST6Gal-1.”
However, Lau does not explicitly teach the production of a stabilized ST6Gal1 by fusion to an antibody Fc domain.
The “Significance” section of Jones teaches the following (emphasis added):
“Sialylation of Fc domain glycans on IgG is now a recognized functional switch between pro- and anti-inflammatory antibody function. Creation and analysis of a B-cell–specific knockout of β-galactoside α-2,6-sialyltransferase 1 (ST6Gal1) revealed that IgG sialylation occurs independently of the B-cell secretory pathway and within the bloodstream after IgG secretion. This finding supports a paradigm for exogenous posttranslational modification of glycoproteins that has profound functional significance for IgG functions modulated by the conserved N-linked glycan within the Fc domain.”
The introduction of Jones further teaches (emphasis added):
“…When administered at high doses, i.v. Ig (IVIg) is an effective anti-inflammatory treatment for autoimmune patients (1). In 2006, it was discovered that the ∼10% of IgG molecules that carry α2,6-linked sialic acids upon the conserved biantennary N-glycans within the Fc domain provided the potent IVIg anti-inflammatory activity in autoimmune disease (2). Indeed, enrichment for the sialylated IgG (sIgG) fraction from IVIg pools increased the efficacy of treatment in mouse models of arthritis 100-fold in an IL-4–dependent fashion through receptors such as CD209 (DC-SIGN) (3, 4)….”
At the page 7209-10 bridging paragraph Jones further demonstrated that the secreted ST6Gal1 is active in murine serum:
“Secreted ST6Gal1 Is Active in the Circulation. Although ST6Gal1 was clearly released into the circulation, we next sought to measure whether it remained a functional sialyltransferase. Sialic acids were removed from mouse serum by mild acid hydrolysis to create substrates for sialylation (20, 21). The asialo-glycoproteins were then separated by SDS/PAGE and transferred to PDVF membranes that were incubated with and without the nucleotide sugar donor CMP-SA and varying amounts of freshly isolated untreated mouse serum or recombinant ST6Gal1 (rST6). Addition of α2,6- and α2,3-linked sialic acid was probed by blotting the membranes with fluorescently conjugated SNA (green) and Maackia amurensis lectin I (MAL-I) (red) lectins, respectively. The blots reveal very low levels of α2,3-sialyltransferase activity and high levels of α2,6-sialyltransferase activity that were independent of exogenously added CMP-SA donor (Fig. 6A). These findings demonstrate not only that is ST6Gal1 present and active in serum, but also that mouse serum itself must contain adequate concentrations of CMP-SA to power the transferase reaction.”
In the Section entitled “Platelets at Least Partially Supply the Nucleotide Sugar Donor,” at page 7210, left col., penultimate paragraph – page 7211, first full paragraph, the teachings of Jones describe how:
(i) platelets release nucleotide sugar donors upon degranulation and lysis, including the nucleotide sugar donor “CMP-sialic acid,” known as “CMP-SA”;
(ii) that recombinant ST6Gal1 is capable of using CMP-SA as a source for the sialic acid to be transferred to a substrate such as an antibody Fc domain; and
(iii) that supernatants from activated, but not resting, platelets provided enough CMP-SA to add α2,6-linked sialic acids to target glycans when used in combination with rST6 (see Fig. 7B).
At page 7211, right col., 2nd full paragraph, Jones concludes:
“A major hurdle to overcome with the notion that any glycosyltransferase, including ST6Gal1, functions within the circulatory environment to remodel glycans on IgG is the source of nucleotide sugar donor required to power the reaction. CMP-SA is the required fuel to power ST6Gal1-mediated additions, yet it has never been found in the circulatory system. In fact, CMP-SA has long been assumed to have a half-life outside of cells that is so short as to preclude its use in enzymatic action, yet the lifetime of extracellular CMP-SA in the rat brain is ∼4 h (32). In our study, we found robust ST6Gal1 activity in serum samples, and this activity did not require the addition of exogenous CMP-SA. Consistent with this observation, we also found an average of 75 μM CMP-SA (range, 59–90 μM) in serum samples from resting mice. Considering that the ST6Gal1 Km for CMP-SA is 92 μM (33), our findings strongly support a model in which sufficient concentrations of CMP-SA are present in the circulation to power the ST6Gal1 reaction.
Interestingly, studies have revealed that the granules within platelets contain high concentrations of both glycosyltransferase enzymes, although not ST6Gal1 and nucleotide sugar donors, including CMP-SA (22, 25). Indeed, granular concentration of CMP-SA is estimated to be 104 pmol/mg granule extract, suggesting that platelet activation and degranulation could be one source of circulatory CMP-SA. We found that not only did in vitro platelet activation provide a donor for ST6Gal1 activity, but also that mice lacking Tomosyn-1, which show a 40% decrease in α-granule release, have a concomitant 40% reduction in IgG sialylation in vivo. These findings firmly establish a central role for platelets as a key contributor to the B-cell–independent sialylation of IgG by ST6Gal1 in the circulation by providing at least one source of CMP-SA; however, it is likely that other CMP-SA sources exist.”
Given the teachings of Lau in view of Jones it would have been obvious to one of ordinary skill in the art that in order for circulatory, recombinant ST6GalI to effectively transfer sialic acid from serum sources, such as CMP-SA, to intravenous immunoglobulin, thereby inducing an anti-inflammatory effect, the intravenously administered recombinant ST6GalI must circulate for an extended period of time such that when CMP-SA becomes available, e.g., as a consequence of platelet activation during acute inflammation, then the recombinant ST6GalI will be present to catalyze the transfer of sialic acid from the CMP-SA to an immunoglobulin Fc glycan.
It was well known in the art that a common way of extending the serum half-life of an intravenously administered protein was via fusion to an antibody Fc domain that will ensure that the fusion protein interacts with the neo-natal FcRn in such a way that the fusion protein has a serum half-life like that of an antibody. This basic concept is described by Henry at col. 21, last full paragraph. Moreover, Figure 1 of Henry illustrates the two commonly used options for making an Fc-fusion protein: joining the fused protein such as the catalytic enzyme (“IDS” or “iduronate 2-sulfatase”) to either the N- and C-termini of the Fc fragment fusion:
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Additionally, at col. 8, 4th full paragraph Henry teaches (emphasis added):
“In some embodiments, provided herein is a polynucleotide comprising a nucleic acid sequence encoding a polypeptide comprising an Fc polypeptide that is linked to an ERT enzyme, an ERT enzyme variant, or a catalytically active fragment thereof, wherein the Fc polypeptide contains one or more modifications that promote its heterodimerization to another Fc polypeptide. In some embodiments, provided herein is a vector comprising the polynucleotide. In some embodiments, provided herein is a host cell comprising the polynucleotide or the vector. In some embodiments, the host cell further comprises a polynucleotide comprising a nucleic acid sequence encoding the other Fc polypeptide. In some embodiments, provided herein is a method for producing the polypeptide described herein, comprising culturing a host cell under conditions in which the polypeptide encoded by the polynucleotide is expressed.”
Given the above, it would have been obvious to one of ordinary skill that fusion of the rST6Gal-1 of Lau to either the N- or C-terminal portion of an antibody Fc domain comprising heavy chain CH2 and CH3 regions was a convenient and well-known strategy for ensuring that the rST6Gal-1 would persistent in the circulation for sufficient time to effectively mediate sialylation of immunoglobulin-G Fc domains, the structure known to mediate the anti-inflammatory activity of IVIg as described by Jones at page 7207, 2nd paragraph of the Introduction.
An additional reason it would have been obvious to one of ordinary skill to make such an Fc- rST6Gal-1 fusion protein was evidenced by the prior art teachings of Washburn. With regard to the beneficial therapeutic effects of intravenous immunoglobulin (IVIg) in inflammatory diseases, Washburn teaches “…the.anti-inflammatory activity of sialylation can be recapitulated using a sialylated Fc fragment derived from IVIg or an IgG1 recombinant antibody (after in vitro sialylation of the Fc) at a 30-fold lower dose than IVIg (24, 27). These results opened the possibility of developing sialylated IVIg and other sialylated antibodies with enhanced anti-inflammatory properties,” see page E1298 left col at last full paragraph, emphasis added. Moreover, the final full paragraph of the Discusion of Washburn concludes “In summary, our results show that highly pure and homogeneous s4-IVIg preparations are critical to obtain a consistently higher level of activity across a variety of animal models under preventive and therapeutic treatment conditions.”
Thus, while it would have been obvious to one of ordinary skill in the art to make a Fc-rST6Gal-1 fusion protein based on the teachings of Lau in view of Jones and Henry for the reasons given above, as further evidenced by the teachings of Washburn the ordinarily skilled artisan would reasonably expect that the anti-inflammatory effect of conventional IVIg antibody treatment (not produced by the bespoke sialylation process of Washburn) could be improved, in vivo, by co-administration of an Fc-rST6Gal-1 fusion protein having a half-life that parallel to that IVIg.
With respect to claim 2, as evidenced by the instant specification at page 39-40 bridging paragraph “ST6GAL1” is also known as a “Beta-galactoside alpha-2,6 sialyltransferase 1”. Thus, the rST6Gal-1 of Lau is also a “Beta-galactoside alpha-2,6 sialyltransferase 1” as recited in claim 2.
With respect to claims 3-5, it further would have been obvious to one of ordinary skill in the art to use human CH2, CH3 and sialyltransferase proteins in the context of such a fusion protein since the human patients suffering from inflammation or allergy are in need of increased antibody Fc sialylation and the use of non-human proteins, such as mouse proteins, would be reasonable expected by the skilled artisan to trigger a therapy defeating human anti-mouse antibody response.
With respect to claims 11-13, it additionally would have been obvious to one of ordinary skill in the art to make a nucleic acid encoding an Fc-ST6GAL1 fusion protein for the purpose of transferring said nucleic acid into an expression vector which would, in turn, facilitate the host cell expression necessary for milligram or gram level production of the encoded fusion protein as described by Henry at section XI, cols. 52-53.
In conclusion, given the teachings of Lau in view of Jones and Henry, and as evidenced by Washburn, it would have been obvious to one of ordinary skill in the art, and one of ordinary skill in the art would have been motivated to produce the Fc-ST6GAL1 fusion proteins, nucleic acids and cells of claims 1-5 and 11-13.
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 1-13 and 14-19 are rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-19 of prior U.S. Patent No. 11674125. This is a statutory double patenting rejection.
Reference claims 1-13 are identical to instant claims 1-13, i.e., reference claims 1-13 and instant claims 1-13 are drawn to the same invention and thus instant claims 1-13 are rejected under 35 U.S.C. 101.
Likewise, reference claims 14-19 differ from instant claims 14-19 only in the use of “[a] multimer comprising” (ref claims) as compared to “a heteromultimer comprising” (instant claims) but this preamble difference has no affect on the structural elements set forth in the body of instant claims 14-19 which are identical to the structural elements set forth in the body of reference claims 14-19. Thus, this minor difference in the preamble language does not affect the scope of the instant claims relative to the reference claims.
Accordingly, reference claims 14-19 and instant claims 14-19 are drawn to substantially the same invention and thus instant claims 14-19 are rejected under 35 U.S.C. 101.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 20 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20-27 of U.S. Patent No. 11674125. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims recite the treatment of various autoimmune/inflammatory diseases which are encompassed in the breadth of the “IgG-mediated disorders” of the instant claims (see instant specification at page 3, lines 13-14 and last two lines; page 16, lines 3-6; page 29, lines 19-25).
Insofar as applicant is able to overcome the rejections set forth above, with respect to treating the breadth of “IgG-mediated disorders” encompassed by claim 20, note that consistent with the teachings of the instant specification at Examples 1, 3, 5, 6 and 8, the potential of sialylation of IgG antibody as a treatment for IgG-mediated autoimmune and inflammatory diseases was understood by the skilled artisan prior to applicant’s first filing date, see e.g., Washburn et al. (Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):E1297-306 and supplemental pages 1-5, cited herewith), e.g., at page E1302, right col., 2nd paragraph – page E1302 to E1303 bridging paragraph; and at supplemental page 5 or 5).
Further note that even diseases that were not clearly classified as “autoimmune” diseases, but nonetheless were diseases believed to be “IgG-mediated disorders” appear to be treatable by increasing sialylation of IgG antibodies.
For example, as described by Bosseboeuf et al. (Front. Immunol. 8:1347, 19 October 2017, pages 1-17, cited herewith), even in the instance where certain diseases were not clearly considered to autoimmune-type diseases, but were still known to be associated with high IgG levels (either monoclonal or polyclonal), such as “Multiple Myeloma” and “monoclonal gammopathy of undetermined significance (MGUS),” sialylated antibodies were still thought to be anti-inflammatory. For example, at Fig. 9 (emphasis added): “A pro-inflammatory microenvironment induces the secretion by malignant plasma cells of high amount of hyposialylated mc IgG which preferentially bind to activating receptors FcγRs (ITAM, blue pathway). To the contrary, sialylated IgGs preferentially bind to the inhibiting receptor FcγRIIb (ITIM, red pathway).”
Likewise, low level of IgG sialylation were known to be associated with the severity of chronic kidney disease, which is a broad genus encompassing both autoimmune CKD and “patients whose CKD is due to other etiologies,” see Barrios et al., J Am Soc Nephrol 27: 933–941, 2016, cited herewith, at page 938, left col., penultimate paragraph. That said, as described by Barrios at page 934, left col., 1st full paragraph, CKD could also be considered an “IgG-mediated disorder:”
“Animal models highlighted the potential role of IgG glycosylation in the pathophysiologic mechanism involved in renal damage. Indeed studies have shown that modulation of
ANCA IgG glycosylation reduces its pathogenicity in mouse ANCA-associated GN.21 Also, IgG Fcg receptor deficiency was found to be renoprotective in a mouse model of diabetic nephropathy.20 Human studies suggest that aberrant glycosylation of the IgA1 is implicated in the deposit and formation of the immunocomplex IgA–IgG in patients with IgA
nephropathy.22,23”
Thus, the teachings of Barrios illustrate yet another IgG-mediated disorder, chronic kidney disease, which is not clearly an autoimmune disorder, could still potentially be treated with a fusion polypeptide as set forth in claim 1.
Insofar as applicant is able to overcome the rejections set forth above, it is the opinion of the undersigned that claims 6-10 and 14-19 would be non-obvious to one of ordinary skill in the art.
Lee-Sundlov et al. (Glycobiology, 2017, vol. 27, no. 2, 188–198, cited herewith) teaches that circulatory mouse GalT can perform certain galactosyltransferase mediated glycosylation (“Thus, the data indicate the ability of circulatory mouse GalT to assemble Type II-LacNAc-O-Bn (i.e. β4GalT), but not Type I-LacNAc-O-Bn (i.e. β3GalT) from GlcNAc-O-Bn,” see page 191, right col., lines 12-14), at page 195, right col., lines 1-7 Lee-Sundlov further teaches (emphasis added):
“Previously, we demonstrated that activated platelets are a functional source of CMP-Sia sugar-donor driving extrinsic sialylation (Lee et al. 2014). Others have shown that platelets also contain a cache of other sugar precursor substrates, such as UDP-GalNAc, UDP-Gal, which is released into circulation upon platelet activation (Wandall et al. 2012; Jones et al. 2016). It still remains to be demonstrated that platelets can likewise drive extrinsic fucosylation or galactosylation events.”
It is the opinion of the undersigned that in light of these teachings it would not have been obvious to one of ordinary skill in the art to make an Fc fusion protein comprising the catalytic domain of galactosyltransferase since the ability of platelets to “drive extrinsic… galactosylation events” was not appreciated by the ordinarily skilled artisan in the same way that platelet produced CMP-Sia sugar-donation was understood to drive extrinsic sialylation in the presence of ST6Gal-1, thereby inducing an anti-inflammatory effect. Moreover, by contrast to the well-established role for extrinsic sialylation in the production of anti-inflammatory Fc domains (as described by Jones), in the opinion of the undersigned it would not have been obvious to the ordinarily skilled artisan that a galactosyltransferase-Fc fusion protein can do the same, or that adding a galactosyltransferase to the ST6Gal1-Fc fusion protein would add to the sialyltransferase-mediated anti-inflammatory effect.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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/YVONNE L EYLER/Director, TC 1600
/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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