DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of Group I, and the antibody binding molecule comprising a HC CDR1 sequence of SEQ ID NO:34, a HC CDR2 sequence of SEQ ID NO:36, a HC CDR3 sequence of SEQ ID NO:38, a LC CDRI1 sequence of SEQ ID NO:40, a LC CDR2 sequence of SEQ ID NO:42, and a LC CDR3 sequence of SEQ ID NO:44 as the p-selectin species and the C3b/C4b Receptor 1 (CR1 or CD35) as the inhibitor cargo domain species, in the reply filed on 9/4/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Upon further consideration, the species requirement for the cargo domain comprising a complement inhibitor is withdrawn.
Applicant’s election corresponds to claim 1, part c). The antibodies of claim 1, parts a) and b) are not under consideration. With respect to claim 1, parts, d)-f), only SEQ ID NO: 10 contains the CDRs for the elected antibody. SEQ ID NOS: 2 and 6 do not. SEQ ID NOS:2 and 6 are not under consideration. With respect to claim 6, SEQ ID NOS: 47 and 49 contain the CDRs for the elected antibody. SEQ ID NOS: 51 and 53 do not. SEQ ID NOS: 51 and 53 are not under consideration.
Claims 9-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2/2/2023.
Claims 1-8 are under consideration.
Drawings
The Petition to Accept Color Drawings filed 8/30/2023 was dismissed 12/4/2023.
Specification
The disclosure is objected to because of the following informalities:
The sequence listing in this submitted under WIPO Standard ST.26. In compliance with these rules, SEQ ID NOS: 21, 22, 30, 31, 42, and 43 have been skipped in the sequence listing. The specification, including the claims, should not reference these sequence identifiers. The actual sequences should be used rather than referencing the sequence identifier. At least for example, all references to SEQ ID NO: 42 should be replaced with the sequence RAN. See at least Table 2 for the RAN sequence and at least paragraphs [0013, 0017, 0021, 0031, 0131, 0171], page 105, and the claims where SEQ ID NO: 42 is referenced in multiple places. The specification and claims should be corrected to remove reference to SEQ ID NOS: 21, 22, 30, 31, 42, and 43.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4 and 7-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Holers et al. (U.S. Patent No. 9,259,488, of record) or Holers et al. (WO 2014/028865, of record).
U.S. Patent No. 9,259,488 and WO 2014/028865 are equivalent documents. The WO document will be referenced.
Holers et al. discloses the fusion protein 3d8bCrry having the amino acid sequence of SEQ ID NO: 32. Pharmaceutical compositions are disclosed. Methods of administering the fusion protein to subjects having a variety of diseases are disclosed. The diseases include ischemia-reperfusion injury, inflammatory disorders, traumatic brain injury, and autoimmune diseases. Methods of treating complement-mediated inflammation by administering a complement inhibitor is disclosed. See at least claims, Example 1, Figures 20 and 22-23, and paragraphs [0036, 0038-0039, 0040-0041, 0061-0062, 0201, 0206-0211, 0237, 0260, 0304, and 0330-0338]. See in particular the end of paragraph [0304].
The elected CDRs of instant SEQ ID NOS: 34, 36, 38, 40, 42, and 44 are present in SEQ ID NO: 32 of Holers et al. See amino acids 60-67 (corresponding to instant SEQ ID NO: 34), 85-92 (corresponding to instant SEQ ID NO: 36), 132-138 (corresponding to instant SEQ ID NO: 38), 191-196 (corresponding to instant SEQ ID NO: 40), 214-216 (corresponding to instant SEQ ID NO: 42), and 252-261 (corresponding to instant SEQ ID NO: 46) of SEQ ID NO: 32. Amino acids 25-271 of SEQ ID NO: 32 have 93.2% identity to amino acids 6-262 of instant SEQ ID NO: 10. The instant application discloses that these CDRs correspond to CDRs for an antibody that binds to p-selectin. See at least Table 2 in the instant specification and instant claim 1, part c). As such, amino acids 35-275 of SEQ ID NO: 32 are considered to be an scFv antibody for p-selectin. A linker at amino acid positions 150-164 of SEQ ID NO: 32 separates the VH from the VL. This antibody anticipates the antibodies of instant claims 1-3.
As SEQ ID NO: 32 is disclosed as being an scFv 3d8b fused to the sequence for Crry (see instant claim 4), the construct of SEQ ID NO: 32 anticipates the instant fusion protein of claim 1, part c), and claim 4, and Holers et al. discloses administering the fusion protein to subjects with the conditions as recited in claims 7-8.
Absent evidence to the contrary, the properties recited in claim 2 would be inherent to the fusion protein of Holer et al.. The instant specification acknowledges that Crry is a C3 convertase inhibitor. See at least paragraph [0313]. Any arguments to the contrary will be viewed as evidence that the claims are not enabled for their scope.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Tomlinson et al. (U.S. Patent Application Publication 2008/0267980) in view of either Holers et al. (U.S. Patent No. 9,259,488) or Holers et al. (WO 2014/028865, of record) and CN101602809B (of record, including machine translation).
Holers et al. is applied as above.
Tomlinson et al. discloses CR1 and CR2 fusion proteins and discusses antibody-complement inhibitor fusions such as Ab-DAF and Ab-CD59. The usefulness of targeting p-selectins is disclosed. See in particular paragraph [0008]. Targeting complement inhibitors to sites of complement activation is disclosed. CR1, DAF, CD59, Crry, and MCP are disclosed. (See instant claim 4.) Their amino acid sequences are disclosed in paragraphs [0665-0666 and 0671-0673]. Treatment of pathogenic diseases and inflammatory conditions by modulating the complement system is disclosed. Treatment of conditions such as asthma, systemic lupus erythematosus, rheumatoid arthritis, ischemia reperfusion injury, and stroke is disclosed. See at least abstract, claims, Figure 1, paragraphs [0008-0009, 0050, 0093-0097, 0194, 0318-0319, 0327, 0628-0629]. Tomlinson et al. does not disclose p-selectin antibodies.
The machine translation of CN101602809B is being relied upon. CN 101602809B discloses a fusion protein comprising an scFv that binds to p-selectin fused to the complement inhibitory protein CD59 (see instant claim 4). Amino acids 1-122 of SEQ ID NO: 1 correspond to the heavy chain and amino acids 133-240 of SEQ ID NO: 1 correspond to the light chain of the anti-P-selectin single chain antibody ScFv. Amino acids 251-323 of SEQ ID NO: 1 correspond to CD59. Pharmaceutical compositions having pharmaceutically acceptable excipients are disclosed. See at least for example claim 1 and paragraphs [0012-0016, 0039-0040, and 0042-0043]. Paragraphs [0039-0049] disclose treating inflammatory responses. Paragraphs [0044-0045] disclose the dosage 200 µg/kg. Paragraph [0081] discloses the construct named pEE14.1/ScFv-CD59 having the form of VL-linker-VH-linker-CD59. Paragraphs [0094-0096] disclose administration in a mouse model of rheumatoid arthritis where inflammation is significantly inhibited as compared with non-targeted complement inhibitors. See also Figure 12. CN101602809B does not disclose a fusion protein of a p-selectin antibody to inhibitors other than CD59 such as CR1, DAF, MCP, and Crry and does not disclose the anti-p-selectin antibody having the CDRs of instant claim 1, part c).
It would have been obvious to administer the fusion protein 3d8bCrry (SEQ ID NO: 32, meeting the sequence limitations of instant claim 1, part c), with Crry as in instant claim 4) of Holers et al. to inhibit the complement pathway and treat associated conditions as suggested by CN101602809B and Tomlinson et al. for similar constructs. It would also have been obvious to substitute the anti-p-selectin scFv antibody as disclosed in Holers et al. (meeting the sequence limitations of instant claim 1, part c)) for the anti-p-selectin scFv antibody in the construct of CN101602809B to arrive at a fusion protein of an anti-p-selectin scFv and CD59 within the scope of the claims and administer this fusion protein to inhibit the complement pathway and treat associated conditions as taught by CN101602809B. It would have been further obvious to fuse the anti-p-selectin scFv antibody as disclosed in Holers et al. (meeting the sequence limitations of instant claim 1, part c)) with any of CR1, MCP, and DAF as suggested by the prior art to arrive at other fusion protein embodiments within the scope of the claims and administer these fusion protein to inhibit the complement pathway and treat associated conditions as taught by Holers et al., CN101602809B, and Tomlinson et al. Ischemia related conditions are complement associated conditions as taught by the prior art. One would have been motivated to do so in order to have additional therapies for treating ischemia related conditions and other complement associated conditions. With respect to claim 2, the specification acknowledges that Crry is a C3 convertase inhibitor. See at least paragraph [0313].
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 1-4 and 7-8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 5 of U.S. Patent No. 11,191,851 (of record) in view of CN101602809B (of record, including machine translation) and Tomlinson et al. (U.S. Patent Application Publication 2008/0267980).
CN101602809B and Tomlinson et al. are applied as above.
The issued claims are directed to a peptide comprising amino acid 1-275 of SEQ ID NO: 32 and a composition comprising SEQ ID NO: 32. SEQ ID NO: 32 in the issued patent corresponds to SEQ ID NO: 32 in Holers et al. (U.S. Patent No. 9,259,488) or Holers et al. (WO 2014/028865, of record) as discussed above.
It would have been obvious to administer the 3d8bCrry fusion protein of issued claim 2 of the ‘851 patent to inhibit the complement pathway and treat inflammation as suggested by Tomlinson et al. for similar constructs. With respect to claim 2, the specification acknowledges that Crry is a C3 convertase inhibitor. See at least paragraph [0313]. It would also have been obvious to substitute the anti-p-selectin scFv antibody in issued claim 1 of the ‘851 patent (meeting the sequence limitations of instant claim 1, part c)) for the anti-p-selectin scFv antibody in the construct of CN101602809B to arrive at a fusion protein of an anti-p-selectin scFv and CD59 within the scope of the claims and administer this fusion protein to inhibit the complement pathway and treat associated conditions as taught by CN101602809B. Ischemia related conditions are complement associated conditions as taught by the prior art. One would have been motivated to do so in order to have additional therapies for treating ischemia related conditions and other complement associated conditions.
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 1-8 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.
The CDRs in claim 1, part c), correspond to the elected p-selectin binding domain. In a minimal embodiment encompassed by the language “at least one CDR,” the antibody can contain a single CDR recited. A single CDR is insufficient to define the antigen-binding domain of an antibody. All six CDRs in claim 1, part c), would be required to define the p-selectin binding domain. At least for example, paragraph [0048] of Cashman et al. (U.S. Patent No. 2018/0346534) discloses an amyloid β antibody having an LCDR2 sequence RAN (identical to instant SEQ ID NO: 42 as currently recited in claim 1, part c), as set forth in instant Table 2). At least for example, SEQ ID NO: 91 (identical to instant EQ ID NO: 34) in Table 5 of Schneewind et al. (U.S. Patent Application Publication 2016/0137749) is disclosed as the HCDR1 of a Staphylococcal Protein A antibody. The individual CDRs recited in claim 1, part c), do not define the structure of an antibody to a p-selectin binding domain. The specification does not disclose any embodiments with less than the six CDRs capable of binding to p-selectin. The specification does not describe the structure of other CDRs that could be combined with any of the named CDRs to form a p-selectin binding site (e.g. other CDRs that could be combined with SEQ ID NO: 34 to form a p-selectin antigen binding site rather than SEQ ID NOS: 36, 38, 40, 42, and 44 as in claim 1, part c). The genus of antibodies claimed is not adequately described. In addition, claim 1, part e), recites “at least 95% identity” to SEQ ID NO: 10 and claim 1, part f) is directed to fragments having at least 80% of the full length sequence of SEQ ID: 10. SEQ ID NO: 10 corresponds to pCold2.12scFv (blocking). See page 105 of the instant specification. Claims 1, parts e) and f), do not require retention of the CDRs responsible for p-selectin binding. SEQ ID NO: 10 is 262 amino acids in length. The claim language permits significant mutation in the CDRs or complete deletion of one or more CDRs. The genus of p-selectin antibodies and fusion proteins containing them are not adequately described.
With respect to SEQ ID NO: 47 (934 amino acids) , SEQ ID NO: 49 (1384 amino acids), SEQ ID NO: 51 (926 amino acids), and SEQ ID NO: 53 (1376 amino acids), the specification does not adequately describe these constructs. It is not known from the specification what amino acid subsequences within these sequences correspond to the p-selectin antibody and what amino acid subsequences correspond to the cargo domain and which cargo domain. Inspection of the sequences reveal histidine tags (see for example amino acids 929-934 of SEQ ID NO: 47) and glycine/serine linkers (see for example amino acids 150-164 and amino acids 272-281 of SEQ ID NO: 47). The specification does not identify the different components within these fusion proteins.
SEQ ID NOS: 34, 36, 38, 40, 42, and 44 are found in instant SEQ ID NO: 10 and are contained in instant SEQ ID NOS 47 and 49 as evidenced by the following alignment. The sequences for SEQ ID NOS: 34, 36, 38, 40,42, and 44 are underlined.
Alignment of instant SEQ ID NO: 10 (Qy) with instant SEQ ID NOS: 47 and 49 (Db):
Qy 6 HHHHHHIEGRHMELGTLEGSEVKLVESGGGLVQPGSSMKLSCTTSGFTFSDYYMAWVRQV 65
|||||||||| ||||||||||||||||||||||||||||||||||||||||
Db 25 HHHHHHIEGR----------EVKLVESGGGLVQPGSSMKLSCTTSGFTFSDYYMAWVRQV 74
Qy 66 PEKGLEWVANINYDGSSAYYLDSFKSRFTISRDNEKNILYLQMSSLKSEDTATYYCARGD 125
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 75 PEKGLEWVANINYDGSSAYYLDSFKSRFTISRDNEKNILYLQMSSLKSEDTATYYCARGD 134
Qy 126 WFVYWGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSMSASLGERVTITCKASQDIN 185
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 135 WFVYWGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSMSASLGERVTITCKASQDIN 194
Qy 186 SYLNWFQQKPGKSPKTLIFRANRLVDGVPSRFSGSGSGQDYSLTISSLEFEDVGIYYCLQ 245
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 195 SYLNWFQQKPGKSPKTLIFRANRLVDGVPSRFSGSGSGQDYSLTISSLEFEDVGIYYCLQ 254
Qy 246 YAEFPFTFGSGTKLEIK 262
|||||||||||||||||
Db 255 YAEFPFTFGSGTKLEIK 271
If this portion of instant SEQ ID NOS: 47 and 49 represents the antibody to p-selectin as disclosed by the instant specification, then this is in conflict with U.S. Patent Nos: 11,191,851 and 9,259,488 and WO 2014/028865. These documents disclose SEQ ID NO: 32 (as discussed above in the prior art and double patenting rejections). Figure 22 in these documents identifies some portions of the SEQ ID NO: 32 sequence such as the location of His tags and linker sequences. These documents do not disclose that SEQ ID NO: 32 (or any portion of it) binds to p-selectin. They disclose anti-C3d antibodies, anti-C3dg antibodies, and anti-iC3b antibodies. See for example paragraphs [0058, 0060, 0129-0130] of WO 2104/028865. These do not appear to be p-selectins. Applicant is requested to clarify the discrepancy between SEQ ID NO: 32 in the prior art and SEQ ID NO: 10 in the instant application and confirm that SEQ ID NO: 32 binds p-selectin. See sequence alignment below.
Alignment of instant SEQ ID NO: 10 (Qy) (262 amino acids) and SEQ ID NO: 32 (Db) (604 amino acids) of U.S. Patent Nos: 11,191,851 and 9,259,488 and WO 2014/028865:
Query Match 93.2%; Score 1303; DB 4; Length 604;
Best Local Similarity 96.1%;
Matches 247; Conservative 0; Mismatches 0; Indels 10; Gaps 1;
Qy 6 HHHHHHIEGRHMELGTLEGSEVKLVESGGGLVQPGSSMKLSCTTSGFTFSDYYMAWVRQV 65
|||||||||| ||||||||||||||||||||||||||||||||||||||||
Db 25 HHHHHHIEGR----------EVKLVESGGGLVQPGSSMKLSCTTSGFTFSDYYMAWVRQV 74
Qy 66 PEKGLEWVANINYDGSSAYYLDSFKSRFTISRDNEKNILYLQMSSLKSEDTATYYCARGD 125
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 75 PEKGLEWVANINYDGSSAYYLDSFKSRFTISRDNEKNILYLQMSSLKSEDTATYYCARGD 134
Qy 126 WFVYWGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSMSASLGERVTITCKASQDIN 185
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 135 WFVYWGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSMSASLGERVTITCKASQDIN 194
Qy 186 SYLNWFQQKPGKSPKTLIFRANRLVDGVPSRFSGSGSGQDYSLTISSLEFEDVGIYYCLQ 245
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 195 SYLNWFQQKPGKSPKTLIFRANRLVDGVPSRFSGSGSGQDYSLTISSLEFEDVGIYYCLQ 254
Qy 246 YAEFPFTFGSGTKLEIK 262
|||||||||||||||||
Db 255 YAEFPFTFGSGTKLEIK 271
With respect to claim 1, parts c) and d), and claim 4, it is unclear what is bound by these constructs in view of the prior art.
In particular, it does not appear that the constructs of SEQ ID NOS: 47, 49, 51, or 53 were tested in any of the experiments. Again, the structural identity or function of the C-terminal sequences in SEQ ID NOS: 47, 49, 51, and 53 is not disclosed by the instant specification. As such, no structure/function correlation has been established to adequately describe the genus of constructs encompassed by the claims. It is unknown which, if any, of the cargo domains comprising a complement inhibitor of claim 4, are bound. Applicant is requested to point to by page and line number to the portion of the specification providing the complete structural (not just CDRs) and functional information about SEQ ID NOS: 47, 49, 51, and 53.
The specification discloses CDRs for three scFv antibodies disclosed as binding to p-selectin. See Table 2. The 2.3scFv, 2.7 scFv, and 2.12scFv antibodies do not adequately describe the genus of antibodies and fusion proteins having the properties of claim 1 and dependent claims. The structural variability of the claimed antibodies and fusion proteins is large. No reasonable structure-function correlation has been established that is commensurate in scope with the claims. The specification does not describe representative examples to support the full scope of the claims.
The p-selectin antibodies of the claims and the fusion proteins containing them lack adequate written description.
Claims 1-8 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 methods as discussed below, does not reasonably provide enablement for all methods of treatment encompassed by the claims. 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 use the invention commensurate in scope with these claims.
As the genus of p-selectin binding domains of claim 1, part c), and fusion proteins containing them are not adequately described as set forth above, the method of treatment claims are not enabled for their scope. One of ordinary skill in the art would not have been able to administer a fusion molecule of unknown structure and function to treat the recited conditions.
Paragraph [0122] of the specification states that the terms “treat” and “prevent” may refer to any delay in onset, reduction in the frequency or severity of symptoms, amelioration of symptoms, improvement in patient comfort or function (e.g. joint function), decrease in severity of the disease state, etc.
Claim 1 requires administering a therapeutically effective amount of a composition to treat a disease or disorder associated with at least one of p-selectin activity and complement signaling. However, no specific therapeutic effect is required. Claims 7-8 recite a wide range of disorders but likewise do not require any particular therapeutic effect. The disorders have widely varying symptoms and characteristics.
Figure 2A-N and paragraphs [0049 and 0285] disclose that PSelscFv-Crry reduced ischemia-reperfusion injury (IRI) in a murine hindlimb model.
Figure 5A-B and paragraphs [0052 and 0291] demonstrate that B.PSelscFv-Crry reduced graft injury in an animal model.
Figure 12 and paragraphs [0059 and 0301] demonstrate that mice subjected to moderately severe traumatic brain injury had the injured portion of the brain targeted by PSelscFv-Crry. No therapeutic effects are disclosed.
Figure 13 and paragraphs [0060 and 0302] demonstrate that mice subjected to stroke using the transient middle cerebral artery ischemia model had the injured portion of the brain targeted by PSelscFv-Crry. No therapeutic effects are disclosed.
Figure 14 and paragraphs [0061 and 0303] show acute neuroprotection by Psel 2.12 following stroke as measured by neurological deficit scores at 24 hours after stroke.
The specification tests 2.12Psel-Crry and 2.3Psel-Crry in an animal model of germinal matrix hemorrhage (GMH). 2.12Psel appears to correspond to SEQ ID NO: 10 linked to the complement inhibitor Crry. 2.12Psel-Crry also blocks PSGL-1 binding (p-selectin function). See page 116. Animals administered 2.12Psel-Crry were not protected from hydrocephalus and trended worse than vehicle treated controls. See paragraph [0374]. Administration of 2.12Psel-Crry provided a significant decrease in C3 deposition and decreased periventricular microgliosis as compared to control. See paragraph [0376]. 2.12 Psel-Crry had an anti-coagulative effect but 2.3Psel-Crry did not in the GMH mice. 2.12Psel-Crry, but not 2.3Psel-Crry, significantly reduced both platelet-neutrophil and platelet-monocyte interactions. See paragraph [0378].
These limited examples do not provide enablement for the breadth of the claims, particularly for the elected p-selectin binding domain antibody of SEQ ID NO: 10 being fused to other cargo domains with different complement inhibitors. The results cannot be extrapolated to support the claimed methods.
At least for example, a symptom of traumatic brain injury is irreversible cognitive deficits due to brain tissue that has been damaged or destroyed. At least for example, a symptom of age-related macular degeneration is vision loss. At least for example, a symptom of the autoimmune disease rheumatoid arthritis is joint damage. There is no evidence of record nor reason to believe that administration of the fusion molecule of claim 1 would restore cognitive deficits, restore vision loss, or reverse joint damage.
In In re Wands (8 USPQ2d 1400 (CAFC 1988)) the CAFC considered the issue of enablement in molecular biology. The CAFC summarized eight factors to be considered in a determination of "undue experimentation." These factors include: (a) the quantity of experimentation necessary; (b) the amount of direction or guidance presented; (c) the presence or absence of working examples; (d) the nature of the invention; (e) the state of the prior art; (f) the relative skill of those in the art; (g) the predictability of the art; and (h) the breadth of the claims.
The breadth of the claims is large with respect to fusion molecules that can be administered, disorders that can be treated, and therapeutic outcomes to achieve. The results for the exemplified embodiments cannot be extrapolated to predict results to support the breadth of the claims. At least for example, the animals models used in the experiments would not have been art recognized models for all diseases (e.g. asthma, hepatitis, glaucoma, see instant claim 7) encompassed by the claims. It would constitute undue experimentation to determine which methods encompassed by the claims would have been operable.
It is suggested that applicant amend the claims to treat a specific condition where the claim requires a specific therapeutic result.
The scope of the claims is not enabled.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 recites “treating a disease or disorder associated with at least one of p-selectin activity and complement signaling.” The term “associated” in claim 1 is a relative term which renders the claim indefinite. The term “associated” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In addition, claim 1 is indefinite in reciting administering a “therapeutically effective amount of a composition” but the claim does not require any particular therapeutic effect. It is unknown what amount must be administered in the absence of a particular therapeutic effect. Finally, claim 1 recites “the p-selectin binding domain comprises at least one” without indicating how multiple p-selectin binding domains are fused with each other and/or the cargo domain. That is, the structure of the compound administered is unclear. It is unclear whether multiple p-selectin domains implicitly require multiple cargo domains. The metes and bounds of the claim cannot be determined.
Claim 3 is confusing. It is unclear how a small molecule or nucleic acid molecule would be fused to the p-selectin binding domain antibody of claim 1. Claim 1 implies a fusion protein. If applicant intended a conjugate or some other structure, the claim language is not clear. See also claim 4 as LNP023 is a small molecule and cemdisaran is a nucleic acid.
Claim 4 is confusing in reciting “(murine equivalent of MCP)” following Crry. It is unclear if this portion of the claim is limited to Crry or whether the parenthetical phrase broadens this embodiment to any murine equivalent of MCP. Generally, parenthetical phrases usually reflect acronyms or other art understood names for the same product and do not include descriptive information. The claim is unclear. In addition, claim 4 indicates that the complement inhibitor comprises “at least one” of the recited compounds. The claim does not indicate how more than one would be fused to the p-selecting binding domain(s) as required in claim 1. That is, the structure of the compound being administered is unclear. The metes and bounds of the claim cannot be determined.
Claim 7 recites “ischemia related condition, including reperfusion injury,” “including germinal matrix hemorrhage (GHM),” “including glaucoma,” and “(including but not limited to viral and bacterial infections, systemic organ involvement).” Claim 8 recites “ischemia related.” The term “related” in claims 7-8 is a relative term which renders the claims indefinite. The term “related” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Examples of disorders are not a limiting definition for what is intended. In addition, the phrase "including" in multiple places renders claim 7 indefinite because it is unclear whether these particular examples limit the broader conditions recited in the claim. See MPEP § 2173.05(d). A broad limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 7 recites broad disease categories and the claim also recites specific conditions which are the narrower statement of the limitation. Claim 7 is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. The metes and bounds of conditions to be treated cannot be determined.
Conclusion
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/Marianne P Allen/Primary Examiner, Art Unit 1647
mpa
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