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 .
Application Status
Claims 1-3 are pending and examined on the merits herein.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1-3 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of producing a sialylated IVIG preparation wherein at least 60% of the branched glycans comprise a terminal sialic acid on both the alpha 1,3 arm and alpha 1,6 arm when the method of claim 1 utilizes an ST6-beta-galactoside alpha-2,6-sialyltransferase 1 (ST6Gal1) having the sequence set forth in amino acid residues 95-416 of SEQ ID NO: 1, does not reasonably provide enablement for the method using an “ST6Gal1” as broadly recited. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described in In re Colianni, 195 USPQ 150 (CCPA 1977) and have been adopted by the Board of Patent Appeals and Interferences in Ex Parte Forman, 230 USPQ 546 (BPAI 1986). Among these factors are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack thereof in the art,
4. the breath of the claims,
5. the amount of direction or guidance present, and
6. the presence or absence of working examples.
The following is an analysis of these factors in relationship to this application.
Applicant discloses a method of producing a disialylated IVIG preparation using the methodology set forth in Example 1. That method utilized specific reagents, in particular an ST6Gal1 sialyltransferase that is defined as SEQ ID NO: 1 (page 33, part B, see constituent in the embedded Table). SEQ ID NO: 1 is shown in Fig. 5A. The specification discloses the ST6Gal1 used in the working example unexpectedly possessed not only the ability to transfer sialic acid using the sialic acid donor CMP-NANA, but also the ability to remove sialic acid (that is, it is also a sialidase). The particular ST6Gal1 used also removed the sialic acid from the alpha 1,3 branch much faster than from the alpha 1,6 branch. Specification, page 34, lines 7-10.
The claims, however, recite a method that utilizes any ST6Gal1 with at least 95% identity to amino acids 95-416 of SEQ ID NO: 1. That is, the claimed method encompasses the use of variants that are both truncated relative to the ST6Gal1 that Example 1 references and that include sequence variation at up to 5% of the amino acid residues, at any position, to any other amino acid. The claimed method therefore encompasses the use of truncations and a large number of sequence variants of the ST6Gal1 set forth in SEQ ID NO: 1 and reported to have been used in the working example.
ST6Gal1 (EC 2.4.99.1) is one member of a family of sialyltransferases found in a variety of mammalian species that transfers sialic acid from cytidine 5’-monophospho-sialic acid (CMP-NANA) to the terminal galactose residues of glycochains through an alpha-2,6-linkage. E.g., reviewed by S. Takashima, Biosci Biotech & Biochem 72:5:1155-67 (2008) (IDS entered 09/25/2020; application 17/03,994). Isoforms with different levels of catalytic activity exist for human ST6-Gal1, with one form encoded by genomic DNA but two forms present when liver RNA is sequenced. E.g., Ma et al., J Biol Chem 272:672-79 (1997) (IDS entered 09/25/2020; application 17/03,994). The activity of ST6-GalI is itself affected by N-linked glycosylation. E.g., Chen & Colley, Glycobiology 10:531-38 (2000) (IDS entered 09/25/2020; application 17/03,994). Truncation studies suggested that the minimal structure needed for transferase activity was contained within residues 97-403. E.g., Id. and Legaigneur et al., J Biol Chem 276:21608-617 (2001) (IDS entered 09/25/2020; application 17/03,994).
Human ST6-Gal1 was known to sialylate intravenous immunoglobulin (IVIG) (which is used therapeutically to treat various autoimmune/inflammatory conditions) in vitro with a preference for the alpha-1,3-arm of the branched Fc glycan found in IVIG, resulting in primarily monosialylated IVIG. E.g., Barb et al., 48:9705-07 (2008) (IDS entered 09/25/2020; application 17/03,994). Methods of in vitro disialylating glycoproteins, including IVIG, by incubating IVIG with a 2,6-sialyltransferase to add sialic acid to terminal galactose molecules on the IVIG were well known in the art by the effective filing date of the claimed invention in May 2013. E.g., US2010/0189714 (IDS entered 09/25/2020; application 17/03,994). As reviewed by Blanche et al. in the “Introduction” section of WO2012/113863 (IDS entered 09/25/2020; application 17/03,994), while there was an art-recognized need to provide preparations of immunoglobulin, including IVIG, that were homogenously and fully sialylated, the prior art methods had not fully met that need since only modest (30%) amounts of disialylated protein generally were attainable. Blanche describes a cell-culture approach in which a monoclonal antibody with mutations in the Fc region was co-expressed in cells that had also been engineered to also express a human alpha-2,6-sialyltransferase and a beta-1,4-galactosyltranferase yielded disialylation on over 80% of the co-expressed, Fc-mutated monoclonal antibody. However, cell-engineering approaches are not practical for disialylating IVIG, which is not a recombinant product.
By 2010, the art was also aware that some alpha-2,6-sialyltranferases from bacteria possessed not only sialyltransferase activity, but also sialidase activity; that is, the same enzyme could both transfer a sialic acid from a donor to acceptor molecule, or remove the sialic acid. E.g., Cheng et al., Glycobiology 20:260-268 (2010) (IDS entered 09/25/2020; application 17/03,994). But while mammalian ST6Gal1 from different species are all sialyltransferases that can utilize the same CMP-NANA donor and incorporate the sialic acid through the same type of 2,6-linkage onto terminal galactose, ST6-Gal1 was not generally thought to possess sialidase activity, only sialyltransferase activity. The original description of human ST6Gal1 expressly indicated that it lacked sialidase activity. Sticher et al., Glycoconjugate J 8:45-54 (1991) (IDS entered 09/25/2020; application 17/03,994). Shortly after the May 2013 effective filing date of the instant application, Engel et al. reported that a particular N-terminal truncation of human ST6-Gal1 (∆89ST6Gal-I, SEQ ID NO: 2) had both sialyltransferase and sialidase activity. US9809835 (IDS entered 09/25/2020; application 17/03,994). That particular truncation variant could be used to disialylate an IgG4 monoclonal immunoglobulin to greater than 88% percent, but only when the reaction was evaluated at 2-8 hours; the levels of disialylation then fell to around 30% after a 48-hour incubation. Id. at Example 10 and Figure 2.
The specification provides a working example in Example 1 on page 33 in which IVIG is sialylated in vitro using the sialyltransferase ST6Gal1 that the Specification indicates is set forth in SEQ ID NO: 1. The IVIG was first galactosylated using B4GalT1 (i.e., beta-1,4-galactosyltransferase) in the presence of the galactose donor UDP-galactose. After the galactosylation had proceeded for 72 hours, CMP-NANA and the ST6Gal1 of SEQ ID NO: 1 were added to the reaction mixture. Figure 2 shows the time-course of glycoform change over a 60-hour period. The highest levels of the “A2F” form; i.e., disialylated IVIG, peaked at between about 60 to less than 70% abundance. As the incubation continued, the level of A2F form decreased to about 30%. Based on the observations that the sialyltransferase ST6Gal1 set forth in SEQ ID NO: 1 adds sialic acid to the alpha-1,3 arm much faster than to the alpha-1,6 arm, and that removal from the alpha-1,3 arm is much faster than removal from the alpha-1,6 arm, the application proposes that the reaction conditions can be varied to preferentially achieve disialylation of IVIG by using intermediate reaction time, enzyme concentration and/or activity, amounts of branched glycans, levels of sialic acid donor, and/or temperature. E.g., Specification at page 23, lines 8-23. Supplementing the sialic acid donor at least once during the reaction is also proposed to lead to preferentially sialylating both arms of the branched glycan. Id. at lines 18-20.
But the ST6Gal1 set forth in SEQ ID NO: 1 and indicated as used in the working example is the full-length form of ST6Gal1. The skilled artisan would not have expected the full-length form of ST6Gal1 as set forth in SEQ ID NO: 1 to have been useful in an in vitro method as described because the full-length enzyme includes a Golgi-retention sequence. The art had previously reported that N-terminal truncations of the first 35, 48, 60, and 89 amino acids were active as sialyltransferases and that truncations that included the conserved motif “QVWxKDS” were not active as sialyltransferases. E.g., Donadio et al., Biochemie 85:311-321 (2003) (cited OA of application 17/032,994; mailed 01/05//2023), see Abstract and the discussion in Section 3.2 on page 314. Nevertheless, the specification still does not identity which, if any, ST6Gal1 sialyltransferases at least 95% identical to residues 95-416 of SEQ ID NO: 1 had sialidase activity and so would be expected to behave with a similar reaction profile that could result in at least 60% disialylated IVIG using the recited method. As noted above, the art shows that for human ST6Gal1, different isoforms and different truncations can affect the sialyltransferase activity of the enzyme. But at the time the invention was made, the art had not yet even come to appreciate that the ST6Gal1 also possessed sialidase activity. And while the specification demonstrates sialidase activity, the working example only indicates sialidase activity for “SEQ ID NO: 1”. No guidance is provided in either the art or the specification as to which residues within SEQ ID NO: 1 provided the sialidase activity required for the instantly recited method.
For these reasons, guidance is lacking to permit the skilled artisan to practice the recited method as broadly as currently claimed without undue experimentation. Accordingly, the claimed method is not commensurate in scope with the enablement provided in the specification, even when considered in view of what was known in the prior art.
Claims 1-3 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 claims contain 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 pre-AIA the inventors, at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Applicant discloses a method of producing a disialylated IVIG preparation using the methodology set forth in Example 1. That method utilizes specific reagents, in particular an ST6Gal1 sialyltransferase that is defined by SEQ ID NO: 1 and that the specification discloses unexpectedly possessed not only the ability to transfer sialic acid using the sialic acid donor CMP-NANA, but also the ability to remove sialic acid (that is, it is also a sialidase). The claims, however, recite a method that utilizes any variant of the ST6-Gal1 sialyltransferase of SEQ ID NO: 1 that comprises residues 95-416 of SEQ ID NO: 1 and has “at least 95% identity.” Thus, the claimed methods recite only a partial structure, but given the requirements regarding the product produced, the claims require those variants to have both sialyltransferase and sialidase activity.
The discussion of the state of the art and Applicant’s disclosure set forth in the rejection under 35 USC 112(a) for lack of enablement is incorporated here in full. Particularly relevant to the instant analysis is that neither applicant nor the art as of the effective filing date had identified what portion of the ST6Gal1 protein of SEQ ID NO: 1 provided the sialidase activity. The specification provides a working example in Example 1 on page 33 using the sialyltransferase ST6Gal1 that the example indicates is set forth in SEQ ID NO: 1. But no additional data is given as to what portion of SEQ ID NO: 1 is necessary for the two functions (sialidase and sialyltransferase) that are essential to produce at least 60% disialylated IVIG as required by the claimed method.
The art of record shows that even for human ST6Gal1, different isoforms and different truncations can affect the activity of the enzyme. The disclosure provides no indication of which residues in SEQ ID NO: 1 were necessary for the activity of a sialidase. The skilled artisan could not envision a priori which residues were essential to the sialidase function of the enzyme and which were not, or to which other amino acids an amino acid at any position might be changed without affecting the sialidase activity of the enzyme. Neither a truncation analysis nor a mutational analysis of the ST6Gal1 of SEQ ID NO: 1 is disclosed in the specification (or in the art for sialidase activity). And the genus of variants encompassed by the “at least 95% identity” language is large, given that up to 16 amino acids, at any combination of positions in SEQ ID NO: 1, could be changed to any of the 19 other amino acids or even deleted.
For these reasons, the single disclosed species is not representative of the genus of variants now encompassed by the claims. Nor can the structure recited be considered a relevant, identifying characteristic since that partial structure was neither known nor disclosed to provide the function required for the ST6Gal1 to work in the method claimed. Therefore, the skilled artisan would not reasonably conclude that the inventors, at the time the application was filed, had full possession of ST6Gal1 variants as broadly recited for use in the claimed method.
Statutory Double Patenting
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 1-3 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-3 of copending Application No. 18218996 (published as US20240167069A1; PTO-892) (reference application). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
Non-Statutory Double Patenting
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-20 of copending Application No. 17909282 (published as US20230374062A1; PTO-892) (reference application).
Although the claims at issue are not identical, they are not patentably distinct because IVIG as claimed comprises a mixture of IgG antibodies as recited in the reference claims, see especially reference claim 16. Therefore, the claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of copending Application No. 18217401 (pub’d as US20240141401A1; PTO-892) (reference application).
Although the claims at issue are not identical, they are not patentably distinct because IVIG as claimed comprises a mixture of IgG antibodies as recited in the reference claims. Therefore, the claims are not patentably distinct. The copending application has the same effective filing date, so a terminal disclaimer is required. See MPEP 804.I.B.1.b.ii.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643