DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 7, 12, 17, and 18 have been canceled.
Claims 1-6, 8-11, 13-16, and 19-30 are pending in the instant application.
Claim 1 is independent and drawn to fusion proteins comprising interleukin-18 binding protein and a Fab that binds serum albumin.
Applicant’s election without traverse of the invention of group I, drawn to fusion proteins, and the species of anti-albumin Fab comprising the six CDRs of SEQ ID NOs: 35-37 and 52-54 in the reply filed on December 22, 2025 is acknowledged.
Claims 19-21 and 25-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 22, 2025.
Claims 1-6, 8-11, 13-16, and 22-24 are under examination in this office action.
Information Disclosure Statement
The IDS forms received 12/30/2025 are acknowledged and the references cited therein have been considered.
Claim Rejections - 35 USC § 112
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 1-6, 8, 10, 11, 13-16, and 22-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant has broadly claimed fusion proteins wherein interleukin-18 binding protein is joined to a Fab fragment of an anti-albumin antibody. The broadest claims recite not particular structural constraints for either member of the claimed fusion proteins, while dependent claims recite additional levels of specific sequence for either the antibody (see for example claims 8-11) or IL-18BP (see claims 15-16). To support such breadth, the specification discloses making a fusion protein between human IL-18BP and an anti-albumin Fab named “SL335” (see working example 1). No working examples concerning production of antibody variants, such as via CDR mutagenesis, appear to be disclosed, and the origin of many of the recited anti-albumin antibody sequences does not appear to be disclosed in the specification as filed.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, 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 genus. See MPEP 2163. In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted: “A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.” The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002). Recent court cases have emphasized the need for correlation between a well-defined structure and recited functional limitations. For example, the courts have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014). Such cases have indicated that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e. the antigen, as knowledge of the chemical structure of an antigen does not provide information as to what an antibody binding that antigen necessarily looks like (i.e. the primary amino acid structure of the antibody). Applicant is reminded that the courts have long ruled that “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. As such, disclosure of a screening assay to test for functional properties of an antibody (such as its ability to bind albumin) does not provide evidence of possession of the antibody itself. Further, courts have long ruled that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005). Also, “A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway et al., see entire selection). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., and Winkler et al., see entire documents). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
Artisans are well aware that knowledge of a given antigen (for instance human serum albumin) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document). Similarly, Lloyd et al. teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding, as their sequencing studies revealed that out of 841 unselected and 5,044 selected antibodies, all but one of the 49 functional VH gene segments was observed (see entire document). Goel et al. disclose the synthesis of three mAbs that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (see entire document). Further, it should be noted that degenerate binding of the same structural motif by antibodies does not require the existence of sequence homology or identity at any of their CDRs or other chemical similarities at the antigen-binding sites; side chain mobility of epitope residues can confer steric and electrostatic complementarity to differently shaped combining sites, allowing functional mimicry to occur (Lescar et al., see entire document, in particular Abstract and Discussion). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequence bound in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen. Indeed, Kanyavuz et al. teach that “Theoretically, under physiological conditions, the human immune system can generate BCRs with 1026 distinct sequences, an astronomical number that is far greater than the calculated number of all B cell clones that can be generated during the lifespan of a healthy human (estimated to be 4 × 1014).
As discussed above, applicant discloses making a fusion protein between human IL-18BP and a Fab fragment of a pre-existing anti-albumin antibody named SL335. As per paragraph [0152] of the instant specification, the Fab of SL335 has a VH-CH1 of SEQ ID NO:10 and a VL-Ck of SEQ ID NO:13. Notably, SEQ ID NO:10 comprises the three VH CDR of SEQ ID NOs: 35-37 while SEQ ID NO:13 comprises the three VL CDRs of SEQ ID NOs:52-54. However, most claims are not limited to any particular sequences, and even for claims like 8 which do recite biological sequences, the CDRs are highly different as can readily be seen by eye when reading the claim (compare for example the VH CDR3 sequences of SEQ ID NOs:24, 28,31, 34, and 37 recited in said claim and note the sequence dissimilarity among the CDR3 sequences strongly indicates the presence of unique, independent clones). Such diversity is problematic as claim 8 as presently written allows for mixing and matching of sequences drawn from unrelated clones, and no data or working examples are present in the specification indicating that such random reassortment of binding domains maintains the necessary structure to ensure antigen binding. Antibodies that bind the same antigen do not necessarily bind the same epitope, or even if it is the same epitope do not bind the epitope in the same way such that combining CDRs from unrelated clones is not reasonably expected to maintain antigen binding as all six are needed as per the teachings of Janeway, with even single amino acid alterations potentially abrogating binding as taught by Rudikoff et al. and Winkler et al. As such there is no reason why artisans would accept that the mixing and matching of disparate structural domains from unrelated antibodies as is presently recited in claims 8, 10, and 11 would yield an antibody that maintains albumin binding in the absence of experimental data demonstrating that such activity actually is present. Further, claim 10 and 11 depend directly from claim 1 which recites no sequence information whatsoever, and thus in addition to only partially defining half of the antigen binding molecule due to the 90% identity language, as written such language allows for mutations within the CDRs which are the very structures responsible for the function of binding albumin. Note also that given the literally astronomical number of distinct antibody sequences that can bind a single antigen as taught by for example Edwards et al., Lloyd et al., and Lescar, the sequences disclosed by applicant do not appear to be a representative number covering the breadth of all anti-albumin antibodies.
Therefore, in view of the breadth of the claims artisans would reasonably conclude that while applicant was in possession SL335 and Fab comprising the same CDRs as found within SL335 (i.e. SEQ ID NOs:35-37 and 52-54) and fusion proteins resulting therefrom, applicant was not in possession of the full breadth of anti-albumin antibodies and fusion proteins comprising such antibodies at the time the instant application was filed. Amendment of the claims to minimally require that the anti-albumin antibodies comprise six fully defined CDRs known to collectively be capable of binding albumin when present as a set of six sequences, such as is presently recited in claim 9 (which is not a party to the instant rejection) is one possible approach to obviating the issues discussed above.
Claims 8, 10, and 11 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Applicant has claimed a genus of fusion proteins comprising interleukin-18 binding protein joined to an Fab fragment of an antibody that binds albumin, wherein the antibody portion is recited as comprising specific biological sequences recited by SEQ ID number. The instant specification discloses a working example wherein the Fab from an anti-albumin antibody named SL335 was joined to IL-18BP (see example 1) and SL335 (VH-CH1 of SEQ ID NO:10, VL-Ck of SEQ ID NO:13) comprises the CDR sequences of SEQ ID NOs:35-37 and 52-54, as well as the VH of SEQ ID NO:60 and the VL of SEQ ID NO:67. Applicant’s claims are broader in scope that such working examples, as visual inspection of claim 8 reveals the presence of biological sequences from multiple unrelated clones (compare for example the strongly dissimilar VH CDR3 sequences of SEQ ID NOs:24, 28,31, 34, and 37 recited in said claim). This is problematic as the CDRs of the VH and VL appear to be randomly selected, specifically for claim 8 artisans can randomly choose any of embodiments 1-6 for the VH CDR sequences and randomly choose any of embodiments 7-12 for the VL CDR sequences.
It is well known in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway et al., see entire selection). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., and Winkler et al., see entire documents). Given that the CDR pairing allowed in the claim come from unrelated clones that even though they bind albumin do not necessarily bind the same epitope of albumin in the same stereochemical configuration and there is no data or working examples indicating such mixing and matching of parts of unrelated antibodies still yield an antibody which maintains antigen binding function. Thus the full extent of what is claimed in instant claim 8 cannot be made without first engaging in additional unpredictable trial and error basic research and experimentation. Additionally, claims 10 and 11 recite 90% identity to VH (claim 10) or VL (claim 11) sequences recited by SEQ ID number, but these claims depend directly from claim 1 which recites no sequence information whatsoever. Given that in order to build an antibody using the tools of molecular biology (which is the only reasonable way to ensure specific recited biological sequences appear where they should in the claimed product) artisans reasonably minimally need six fully defined CDR sequences (see for example Janeway and routine antibody humanization techniques in general) such antibodies cannot be made without undue experimentation. This is because more than half of the required sequence information is missing, and therefore reads upon essentially random sequence and the 90% identity allows for mutations to occur within the CDR sequences which actually are present. Given that CDR changes as small as a single animo acid can abrogate binding as taught by for example Rudikoff et al., and Winkler et al., artisans cannot reasonably make such antibodies without extensive unpredictable research and experimentation.
Therefore, in view of the breadth of the claims, the teachings of the art, and the guidance ad direction of the specification and working examples, artisans would be unable to make the breadth of what was been presently claimed without first engaging in additional unpredictable basic science research and experimentation, and logically of the product cannot be made it cannot be used.
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 1-5, 8-11, 13-16, and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Rubenstein et al. (US 2011/0177065) in view of Cha (US2016/0376350).
Rubenstein et al. disclose IL18BP fused to immunoglobulin Fc domains to extend half life when administered to patients as part of disease treatment methods (see entire document, particularly the abstract, claims, paragraphs [0013], [0078], and [0079], and most particularly claim 9). Notably, as per paragraph [0067] the term “fused protein” means IL-18BP fused with another protein to extend residence time in body fluids, with immunoglobulins being given as an example of such half-life extending proteins. Further, Rubenstein et al. disclose in paragraph [0075] that the sequence of IL-18BP is to be taken from WO99/09063 and as evidenced by the enclose sequence alignment the ‘063 WIPO publication discloses a polypeptide 100% identical to instant SEQ ID NO:7. Thus, the IL-18BP fusion proteins disclosed by Rubenstein et al. comprise instant SEQ ID NO:7. The fusion proteins of Rubenstein et al. are further disclosed as comprising linkers between the elements (see particularly paragraph [0078]) and as being present in pharmaceutical compositions and kits (see for example paragraphs [0086-0102]). Such teachings differ from what has been presently claimed in that Rubenstein et al do not disclose fusion proteins comprising antibodies or Fab fragments thereof that bind albumin.
Cha discloses that fusing a scFv that binds albumin to a molecule of interest has the advantages of extending serum half life similar to Fc domains and provides the advantage of allowing low cost expression of such fusion proteins in bacteria (see entire document, particularly the left column of page 2). In particular, Cha discloses fusions comprising the SL335 Fab which binds albumin, and that the fusion between the molecule of interest and the Fab can be made to either the N or C termini of either the heavy or light chain of the Fab (see particularly paragraph [0015] as well as Figure 4). As has been discussed earlier in this office action, the SL335 Fab comprises the CDRs of SEQ ID NOs:35-37 and 52-54, the VH of SEQ ID NO:60, the VL or SEQ ID NO:67, the heavy chain constant domain of SEQ ID NO:68, the light chain constant domain of SEQ ID NO:69, and VH-CH1 of SEQ ID NO:10, and the VL-Ck of SEQ ID NO:13 (see also enclosed sequence alignments). Pharmaceutical compositions and kits comprising such fusion proteins are disclosed (see for example paragraphs [0024-0028] as well as working examples 1-(16), 1-(18), 1-(19), 2-(3), and 2-(8)). The molecules of interest to which SL335 is joined to extend half life include a wide variety of well known biological proteins including interleukin binding proteins (see particularly paragraph [0023] as well as claims 11, 23, and 26) and working examples are disclosed concerning fusions to human growth hormone (example 1-(9)), GSCF (example 1-(10)), and IFNbeta which (example 1-(11)) comprise linker sequences between the Fab and molecule of interest (see also claim 9). Indeed, Cha et al. expressly teaches that fusion proteins utilizing his SL335 antibody are to be known as “anti-Serum Albumin Fab-Associated (SAFA) technology” and that it is to be used as a platform to develop long-acting biotherapeutics (see particularly paragraph [0030]).
Therefore, it would have been obvious to artisans to substitute the Fc in the IL18BP fusion construct of Rubenstein et al. for SL335 Fab that binds albumin as taught by Cha in order to maintain long serum half-life while gaining the advantage of lower cost production in bacterial expression systems as taught by Cha et al. Artisans would have more than a reasonable expectation of success in making such a substitution given the large number of fusion proteins to disparate biological molecules of interest as taught in the working examples of Cha and the fact that Cha explicitly teaches fusion constructs comprising interleukin binding proteins are encompassed by his invention.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Rubenstein et al. (US 2011/0177065) in view of Cha (US2016/0376350) as applied to claims 1-5, 8-11, 13-16, and 22-24 above, and further in view of Chen et al.
The inventions rendered obvious by the combined teachings of Rubenstein et al. and Cha have been discussed above and differ from what is presently claimed in that while linker sequences are disclosed as being present in their fusion constructs, the exact linkers as recited by SEQ ID number in claim 6 do not appear to be disclosed.
Chen et al. disclose a wide variety of linkers used in fusion proteins, and teach that the sequence GGGGS is particularly attractive in linkers as it is known to increase the stability of folding as well as improve biological activity when used in fusion constructs (see entire document, most particular Table 3, and note that instant SEQ ID NO:72 is GGGGS).
Therefore, it would have been obvious to artisans to use linkers including GGGGS in fusion constructs comprising SL335 and IL-18BP in order to gain the advantages of increased stability and increased biological activity as taught by Chen et al.
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 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.
Claims 1-5, 8-11, 13-16, and 22-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9,9879,077 in view of Rubenstein et al. (US 2011/0177065) and in view of Cha (US2016/0376350).
The issued claims of the ‘077 patent recite Fab that bind albumin as well as fusion proteins comprising said Fab, wherein the Fab has biological sequences which are identical to those as recited in the instant claims (i.e. they are those of the SL335 Fab, see enclosed sequence alignments). The claimed fusion protein are disclosed as comprising linkers (see for example claims 8 and 14) and as comprising interleukin binding proteins joined to the anti-albumin Fab (see particularly claim 10). Pharmaceutical compositions comprising fusion proteins are explicitly claimed (see issued claim 18). The issued claims differ from what is presently claimed in that the interleukin binding protein is not recited as being “interleukin-18 binding protein” and in that the location of wherein the fusion partner is joined to the anti-albumin Fab is not specified in the issued claims.
Rubenstein et al. disclose IL18BP fused to immunoglobulin Fc domains to extend half life when administered to patients as part of disease treatment methods (see entire document, particularly the abstract, claims, paragraphs [0013], [0078], and [0079], and most particularly claim 9). Notably, as per paragraph [0067] the term “fused protein” means IL-18BP fused with another protein to extend residence time in body fluids, with immunoglobulins being given as an example of such half-life extending proteins. Further, Rubenstein et al. disclose in paragraph [0075] that the sequence of IL-18BP is to be taken from WO99/09063 and as evidenced by the enclose sequence alignment the ‘063 WIPO publication discloses a polypeptide 100% identical to instant SEQ ID NO:7. Thus, the IL-18BP fusion proteins disclosed by Rubenstein et al. comprise instant SEQ ID NO:7. The fusion proteins of Rubenstein et al. are further disclosed as comprising linkers between the elements (see particularly paragraph [0078]) and as being present in pharmaceutical compositions and kits (see for example paragraphs [0086-0102]).
Cha discloses that fusing a scFv that binds albumin to a molecule of interest has the advantages of extending serum half-life similar to Fc domains and provides the advantage of allowing low cost expression of such fusion proteins in bacteria (see entire document, particularly the left column of page 2). In particular, Cha discloses fusions comprising the SL335 Fab which binds albumin, and that the fusion between the molecule of interest and the Fab can be made to either the N or C termini of either the heavy or light chain of the Fab (see particularly paragraph [0015] as well as Figure 4). As has been discussed earlier in this office action, the SL335 Fab comprises the CDRs of SEQ ID NOs:35-37 and 52-54, the VH of SEQ ID NO:60, the VL or SEQ ID NO:67, the heavy chain constant domain of SEQ ID NO:68, the light chain constant domain of SEQ ID NO:69, and VH-CH1 of SEQ ID NO:10, and the VL-Ck of SEQ ID NO:13 (see also enclosed sequence alignments). Pharmaceutical compositions and kits comprising such fusion proteins are disclosed (see for example paragraphs [0024-0028] as well as working examples 1-(16), 1-(18), 1-(19), 2-(3), and 2-(8)). The molecules of interest to which SL335 is joined to extend half-life include a wide variety of well-known biological proteins including interleukin binding proteins (see particularly paragraph [0023] as well as claims 11, 23, and 26) and working examples are disclosed concerning fusions to human growth hormone (example 1-(9)), GSCF (example 1-(10)), and IFNbeta which (example 1-(11)) comprise linker sequences between the Fab and molecule of interest (see also claim 9). Indeed, Cha et al. expressly teaches that fusion proteins utilizing his SL335 antibody are to be known as “anti-Serum Albumin Fab-Associated (SAFA) technology” and that it is to be used as a platform to develop long-acting biotherapeutics (see particularly paragraph [0030]).
Therefore, it would have been obvious to artisans to use IL-18BP as the specific interleukin binding proteins in the fusion proteins claimed in the ‘077 patent. Artisans would be motivated to do so in order to gain the advantages of maintaining long serum half-life as compared to Fc while gaining the advantage of lower cost production in bacterial expression systems as taught by Cha et al. Artisans would have more than a reasonable expectation of success in making such a substitution given the large number of fusion proteins to disparate biological molecules of interest explicitly claimed in the ‘077 patent, the number of working examples to disparate biological molecule of interest as taught by Cha., and the fact that fusion proteins of anti-albumin Fab to interleukin binding proteins generically are present in the issued claims of the ‘077 patent.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9,9879,077 in view of Rubenstein et al. (US 2011/0177065) and in view of Cha (US2016/0376350) as applied to claims 1-5, 8-11, 13-16, and 22-24 above, and further in view of Chen et al.
The obvious variations of the issued claims in view of the prior art have been discussed above and differ from what is presently claimed in that while linker sequences are disclosed as being present in their fusion constructs, the exact linkers as recited by SEQ ID number in claim 6 do not appear to be disclosed.
Chen et al. disclose a wide variety of linkers used in fusion proteins, and teach that the sequence GGGGS is particularly attractive in linkers as it is known to increase the stability of folding as well as improve biological activity when used in fusion constructs (see entire document, most particular Table 3, and note that instant SEQ ID NO:72 is GGGGS).
Therefore, it would have been obvious to artisans to use linkers including GGGGS in fusion constructs comprising SL335 and IL-18BP in order to gain the advantages of increased stability and increased biological activity as taught by Chen et al.
Claims 1-5, 8-11, 13-16, and 22-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 10,618,953 in view of Rubenstein et al. (US 2011/0177065) and in view of Cha (US2016/0376350).
The issued claims of the ‘953 patent recite methods of increasing soluble expression in E coli (independent claims 1, 6, and 7) and increasing in vivo half-life (independent claims 8 and 11) by genetically fusing an Fab that binds albumin to a biological molecule of interest, wherein the Fab has biological sequences which are identical to those as recited in the instant claims (i.e. they are those of the SL335 Fab, see enclosed sequence alignments). The fusion proteins of the issued methods are disclosed as comprising linkers (see for example claims 9 and 12) and as comprising interleukin binding proteins joined to the anti-albumin Fab (see particularly claims 5, 10, and 13). The issued claims differ from what is presently claimed in that the interleukin binding protein is not recited as being “interleukin-18 binding protein” and in that the location of wherein the fusion partner is joined to the anti-albumin Fab is not specified in the issued claims.
Rubenstein et al. disclose IL18BP fused to immunoglobulin Fc domains to extend half life when administered to patients as part of disease treatment methods (see entire document, particularly the abstract, claims, paragraphs [0013], [0078], and [0079], and most particularly claim 9). Notably, as per paragraph [0067] the term “fused protein” means IL-18BP fused with another protein to extend residence time in body fluids, with immunoglobulins being given as an example of such half-life extending proteins. Further, Rubenstein et al. disclose in paragraph [0075] that the sequence of IL-18BP is to be taken from WO99/09063 and as evidenced by the enclose sequence alignment the ‘063 WIPO publication discloses a polypeptide 100% identical to instant SEQ ID NO:7. Thus, the IL-18BP fusion proteins disclosed by Rubenstein et al. comprise instant SEQ ID NO:7. The fusion proteins of Rubenstein et al. are further disclosed as comprising linkers between the elements (see particularly paragraph [0078]) and as being present in pharmaceutical compositions and kits (see for example paragraphs [0086-0102]).
Cha discloses that fusing a scFv that binds albumin to a molecule of interest has the advantages of extending serum half-life similar to Fc domains and provides the advantage of allowing low cost expression of such fusion proteins in bacteria (see entire document, particularly the left column of page 2). In particular, Cha discloses fusions comprising the SL335 Fab which binds albumin, and that the fusion between the molecule of interest and the Fab can be made to either the N or C termini of either the heavy or light chain of the Fab (see particularly paragraph [0015] as well as Figure 4). As has been discussed earlier in this office action, the SL335 Fab comprises the CDRs of SEQ ID NOs:35-37 and 52-54, the VH of SEQ ID NO:60, the VL or SEQ ID NO:67, the heavy chain constant domain of SEQ ID NO:68, the light chain constant domain of SEQ ID NO:69, and VH-CH1 of SEQ ID NO:10, and the VL-Ck of SEQ ID NO:13 (see also enclosed sequence alignments). Pharmaceutical compositions and kits comprising such fusion proteins are disclosed (see for example paragraphs [0024-0028] as well as working examples 1-(16), 1-(18), 1-(19), 2-(3), and 2-(8)). The molecules of interest to which SL335 is joined to extend half-life include a wide variety of well-known biological proteins including interleukin binding proteins (see particularly paragraph [0023] as well as claims 11, 23, and 26) and working examples are disclosed concerning fusions to human growth hormone (example 1-(9)), GSCF (example 1-(10)), and IFNbeta which (example 1-(11)) comprise linker sequences between the Fab and molecule of interest (see also claim 9). Indeed, Cha et al. expressly teaches that fusion proteins utilizing his SL335 antibody are to be known as “anti-Serum Albumin Fab-Associated (SAFA) technology” and that it is to be used as a platform to develop long-acting biotherapeutics (see particularly paragraph [0030]).
Therefore, it would have been obvious to artisans to use IL-18BP as the specific interleukin binding proteins in the fusion proteins recited in the methods of the ‘953 patent. Artisans would be motivated to do so in order to gain the advantages of maintaining long serum half-life as compared to Fc while gaining the advantage of lower cost production in bacterial expression systems as taught by Cha et al. Artisans would have more than a reasonable expectation of success in making such a substitution given the large number of fusion proteins to disparate biological molecules of interest explicitly recited in the ‘953 patent, the number of working examples to disparate biological molecule of interest as taught by Cha., and the fact that fusion proteins of anti-albumin Fab to interleukin binding proteins generically are present in the issued claims of the ‘953 patent.
Additionally, it is noted that the issued ‘953 claims are drawn to methods whereas the instant claims are directed to products. However, a method comprising a product always has additional limitations, and therefore is narrower in scope, that the product itself. Further, there is no restriction requirement which necessitated separation of the instant application from that which gave rise to the ‘953 patent, and indeed as evidenced by the filing receipt of 6/4/2024 in the instant application there is no relationship whatsoever between the instant application and that which gave rise to the ‘953 patent. As has been made abundantly clear in recent court decisions, including Pfizer v. Teva and Amgen Inc. v. F. Hoffman-La-Roche Ltd., “the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.” Given that the instant application is not a divisional of the application which gave rise to the issued patent, any restriction requirements (or the lack thereof) appearing in unrelated lineages do not serve to shield the instant application and therefore the instant rejection has been set forth.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 10,618,953 in view of Rubenstein et al. (US 2011/0177065) and in view of Cha (US2016/0376350) as applied to claims 1-5, 8-11, 13-16, and 22-24 above, and further in view of Chen et al.
The obvious variations of the issued claims in view of the prior art have been discussed above and differ from what is presently claimed in that while linker sequences are disclosed as being present in their fusion constructs, the exact linkers as recited by SEQ ID number in claim 6 do not appear to be disclosed.
Chen et al. disclose a wide variety of linkers used in fusion proteins, and teach that the sequence GGGGS is particularly attractive in linkers as it is known to increase the stability of folding as well as improve biological activity when used in fusion constructs (see entire document, most particular Table 3, and note that instant SEQ ID NO:72 is GGGGS).
Therefore, it would have been obvious to artisans to use linkers including GGGGS in fusion constructs comprising SL335 and IL-18BP in order to gain the advantages of increased stability and increased biological activity as taught by Chen et al.
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 1-6, 8, 9, 15, 16, and 23 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-6, 8, 9, 15, 16 and 23 of copending Application No. 18/895,157. This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
Specifically, on 1/3/2025 applicant amended the claims of the ‘157 application to be word for word identical to that of the most recent claim set in the instant application for the indicated claims. For example, instant and copending claim 1 are the same, and this relationship holds for all indicated claims. Since the wording is the same there can be no difference in scope. Further, the ‘157 application was filed on 9/24/2024 as a continuation of the instant application which is before any restriction requirement was set forth in the instant application.
No claims are allowable.
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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641