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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Election/Restrictions
Applicant's election with traverse of Group I in the reply filed on 5/29/26 is acknowledged. The traversal is on the ground(s) that Applicant believes the Wolf reference describes BiTE molecules in a substantially different context, as antibody constructs, in which one arm binds CD3 on T cells and the other binds a target cell such as CD19 on B cells. Wolf does not disclose or suggest replacing the target -cell antibody binding arm with a conformational autoantigen, nor does it disclose a PLA2R-derived fragment. Kao does not teach BiTE molecules, T-cell engagers, or therapeutic fusion proteins. This is not found persuasive because Applicant is arguing the references individually, without addressing the teachings as a whole. As indicated in MPEP 2145, One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The requirement is still deemed proper and is therefore made FINAL.
Claim Status
The amendments filed 5/29/26 are acknowledged. Claims 1-16 are pending. Claim 10 is amended.
Claims 13-14 and 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 5/29/26.
Claims 1-12 and 15 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statements filed on 10/23/23 and 5/13/26 have been considered. Signed copies are enclosed.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Notice to Comply with 37 CFR §§ 1.821—1.825
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 C.F.R. §§ 1.821-1.825 for the following reason(s): Figure 7 recites amino acid sequences without proper reference to the corresponding sequence identifiers ("SEQ ID NO:__").
To be considered fully responsive, any reply to this action must address these deficiencies, as this requirement will not be held in abeyance.
Claim Objections
Claim 10 is objected to because of the following informalities: the phrase “selected from (i) (Gly-Gly-Gly-Gly-Ser)n, wherein n = 1, 2, 3, or 4 (SEQ ID Nos: 9, 10, 11, and 12, respectively) and (ii) (Gly)m, wherein m = 6, 7, or 8 (SEQ ID Nos 13, 14, and 15, respectively) should be amended to recite only the relevant SEQ ID NO. For example: “selected from SEQ ID NO:9-15”. Appropriate correction is required.
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 1-4, 6, 8-12 and 15 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
The instant claims are drawn to a fusion protein comprising an N-terminal fragment of the phospholipase A2 receptor (PLA2R) extracellular domain and an antigen binding fragment of an anti-CD3 antibody. The N-terminal fragment of PLA2R can be a cysteine rich domain (CysR), and can comprise additional domains. The component of an anti-CD3 antibody is not adequately described, and therefore the fusion protein is not adequately described.
The specification and claims identify species blinatumomab, muromonab, and scFvs of SEQ ID Nos: 2-5. However the claim encompasses any antibody that can functionally bind to CD3, including at any epitope on the protein. These antibodies, and therefore the resulting fusion proteins have no correlation between their structure and function. The claim requires that the peptide exhibit antifungal and/or antibacterial activity, but the specification provides no guidance regarding which variants or fragments are capable of the required function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
With the exception of blinatumomab, muromonab, and scFvs of SEQ ID Nos: 2-5, the skilled artisan cannot envision the detailed chemical structure of the encompassed antibodies and antibody fragments, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
Regarding the encompassed antibodies and fragments thereof, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation 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. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of antibodies that have specific required functions. The specification discloses blinatumomab, muromonab, and scFvs of SEQ ID Nos: 2-5 within the instant claims scope that also have the required functions, but the specification does not provide any guidance as to which protein structures, sequences or individual amino acids are necessary, or can be varied, within the antibodies or fragments thereof and still retain the required functions.
Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself even when preparation of such an antibody would be routine and conventional. Amgen, 872 F.3d at 1378-79. A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
The prior art recognizes that the antigen binding by antibodies requires precise orientation of the complementarity determining region (CDR) loops in the variable domain to establish the correct contact surface. For example, Vattekatte, (PeerJ. 2020 Mar 6:8:e8408. doi: 10.7717/peerj.8408. eCollection 2020.) teach that antigen binding in heavy chain only antibodies, (HCAbs) is mediated by only three CDR loops from the single variable domain (VHH) at the N-terminus of each heavy chain, (see abstract). The Vattekatte et al further teach that the amino acid length distribution in different regions of VHH (see Fig. S7) shows diversity in CDR lengths, and that most diversity in CDR3, (see page 7 and 19). However, the prior art also recognizes that a single protein can be bound by a very large and structurally diverse genus of antibodies (i.e., there is no common structural relationship even for antibodies that bind to the same protein, epitope, or overlapping epitopes). For example, Edwards et al. (Mol Biol. 2003 Nov 14;334(1):103-18) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive 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 table 2, figure 2).
Lloyd et al. (Protein Eng Des Sel. 2009 Mar;22(3):159-68. Epub 2008 Oct 29.) 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, (abstract). The Lloyd et al reference further teaches that in their studies, of the 841 unselected and 5,044 selected antibodies sequenced, all but one of the 49 functional VH gene segments was observed, and that there are on average about 120 different antibodies generated per antigen (page 167, column 1). Said reference also teaches that a wide variety of VH and VL pairings further increase diversity. (page 159, column 2).
Goel et al. (J Immunol. 2004 Dec 15;173(12):7358-67) teach that three mAbs that bind to the same short (12-mer) peptide, exhibit diverse V gene usage, indicating their independent germline origin. Said reference further teaches that two of these mAbs recognize the same set of amino acid residues defining the epitope (alternate amino acid residues spread over the entire sequence), however, the relative contribution of each set of residues in the peptide showed significant variation. The reference notes that all of the mAbs do not show any kind of V gene restriction among themselves, implying variable paratope structure, despite that two of these mAbs bind to the peptide through a common set of residues. (See entire reference).
Khan et al. (J Immunol (2014) 192 (11): 5398–5405) teach that two structurally diverse germline mAbs recognizing overlapping epitopes of the same short peptide do so in different topologies, the antibodies possessing entirely different CDR sequences. Said reference teaches that unrelated mAbs structurally adjust to recognize an antigen, indicating that the primary B cell response is composed of BCRs having a high degree of structural adaptability. Said reference also teaches that the common epitope(s) also adopt distinct conformations when bound to different mAbs, with the higher degree of structural plasticity inherent to the mAbs. Said reference further teaches “It has been shown that both the framework region and the CDRs have a considerable amount of inherent conformational plasticity...Therefore, it is not surprising that distinct germline Abs recognize the same epitope by rearranging the CDR conformations. This may well have implications of Ag specificity beyond the naive BCR repertoire, because Kaji et al... .have shown in a recent report that the B cell memory can contain both germline-encoded and somatically mutated BCRs.” (See entire reference).
Poosarla et al. (Biotechnol Bioeng. 2017 June ; 114(6): 1331–1342) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Rabia, et al. (Biochem Eng J. 2018 Sep 15:137:365-374. Epub 2018 Jun 5) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al. report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Rabia et al. thus teach that affinity and specificity are not necessarily correlated and that an increase in affinity does not indicate an increase in specificity (Fig. 3; p. 368, col. 1, section 3,1st full paragraph to col. 2, 2nd full paragraph).
Therefore, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: …To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claim Rejections - 35 USC § 112(b)
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 1-12 and 15 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.
In claim 1, the term “N-terminal fragment” renders the claim indefinite. It is unclear what structure must be present to be a “fragment”. For example, a “fragment” can be a single amino acid, or can require a specific number of amino acids. The scope of the “fragment” is therefore indefinite.
Claims 2-4 recites a “Cysteine-rich domain” “fibronectin type-2 domain” and “C-type lectin-liked domains” without describing the structures necessary for the domains. There are no criteria set forth to determine which amino acid sequences would be encompassed by these terms.
Claim 3 recites “an amino acid sequence of SEQ ID NO:1” and claim 10 recites “amino acid sequence which is selected from”. It is unclear from the phrasing if the term “an amino acid sequence” refers to the entire sequence of the SEQ ID NO, or if the phrase encompasses any two amino acids linked in sequence that are present in SEQ ID NO.
Claim 4 recites the limitation "the single". There is insufficient antecedent basis for this limitation in the claim.
Claim 4 recites “from 1 to 7 C-type lectin-like domains (CTLD1-7)”. It is unclear if the name of the domain includes “from 1 to 7”, which would be indicated by (CTLD1-7), or if this language references the number of domains. If the latter is applicable, it is unclear if the domains are the same domain repeated up to 7 times, or if there are seven separate domains with different structures.
Claim 11 recites “purification tag”. However, this term is not defined in the specification and it is unclear what criteria must be met to differentiate “purification” tags from other protein tags.
Claim 15 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claim 15 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: proteins and nucleic acids do not share any structural similarities because they are made from different molecules. Further, the two molecule types do not have a common use due to differences in structure and function.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claims depending from the rejected claims do not remedy the deficiency and therefore are also rejected.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 1-4, 6, 8-10 and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gill et al (CA 3098865A1; filed 5/2/19; published 11/7/19) in view of Wolf et al ("BiTEs: bispecific antibody constructs with unique anti-tumor activity", DRUG DISCOVERY TODAY, vol. 10, no. 18, 15 September 2005, pages 1237-1244).
The instant claims are directed to a fusion protein comprising: an N-terminal fragment of the phospholipase A2 receptor (PLA2R) extracellular domain, and an antigen-binding fragment of an anti-CD3 antibody.
Instant claim 2 is directed to the fusion protein according to claim 1, wherein the N-terminal fragment of the PLA2R extracellular domain comprises the Cysteine-rich domain (CysR).
Instant claim 3 is directed to the fusion protein according to claim 2, wherein said CysR has an amino acid sequence of SEQ ID NO:1.
Instant claim 4 is directed to the fusion protein according to claim 2, wherein said N-terminal fragment of the PLA2R extracellular domain further comprises the single fibronectin type-2 domain (FnII) and from 1 to 7 C-type lectin-like domains (CTLD1-7).
Instant claim 5 is directed to the fusion protein according to claim 1, wherein said anti-CD3 antibody is blinatumomab or muromonab.
Instant claim 6 is directed to the fusion protein according to claim 1, wherein said antigen- binding fragment of an anti-CD3 antibody is scFv.
Instant claim 7 is directed to the fusion protein of claim 6, wherein said scFv is selected from SEQ ID NOs:2, 3, 4 and 5.
Instant claim 8 is directed to the fusion protein according to claim 1, further comprising a peptide linker interposed between the PLA2R extracellular domain and the anti-CD3 antigen-binding fragment.
Instant claim 9 is directed to the fusion protein according to claim 8, wherein said linker contains from 5 to 20 amino acid residues.
Instant claim 10 is directed to the fusion protein according to claim 9, wherein said linker comprises an amino acid sequence which is selected from (i) (Gly-Gly-Gly- Gly-Ser)n, wherein n = 1, 2, 3 or 4 (SEQ ID Nos:9, 10, 11 and 12, respectively) and (ii) (Gly)m, wherein m = 6, 7 or 8 (SEQ ID Nos 13, 14 and 15, respectively).
Instant claim 11 is directed to the fusion protein according to claim 1, which further comprises a purification tag.
Instant claim 12 is directed to the fusion protein according to claim 11, wherein said purification tag is a polyhistidine fragment.
Instant claim 15 is directed to a pharmaceutical composition comprising a fusion protein according to claim 1, a nucleic acid molecule encoding said fusion protein or an expression vector comprising said nucleic acid, together with pharmaceutically acceptable excipients.
Gill teaches a chimeric autoantibody receptor (CAAR) wherein the CAAR comprises a phospholipase A2 receptor (PLA2R) autoantigen or fragment thereof (see e.g. page 2, lines 9-12). The PLA2R can comprise an extracellular domain, a C-type lectin domain 1 and 2, and a fibronectin type II domain (see e.g. page 4, lines 5-23, and figure 2). The CysR domain can be encoded by SEQ ID NO:1, which is identical to instant SEQ ID NO:1 (see e.g. page 22, lines 22-30). Gill teaches a variety of suitable linkers, including a GS linker (see e.g. page 26, lines 4-6), which can have the sequence of GGGGSGGGGS (see e.g. page 28, lines 5-11). Gill teaches that the CAAR can be administered in a genetically modified T-cell (see e.g. page 3, lines 3-10). The cell can express and induce killing of B cells expressing autoantibodies (see e.g. page 5, line 30 to page 6, line 6)
Gill does not disclose a molecule with a CD3 antibody or scFv.
Wolf discloses bispecific T cell engager (BiTE) molecules that are bispecific single-chain antibodies for the polyclonal activation and redirection of cytotoxic T cells against pathogenic target cells (refer to abstract; pg 1242-1243; Fig. 2-4). Said molecules have outstanding therapeutic potential for the treatment of malignant diseases, for example, MT103 is a CD19-specific BiTE comprising an anti-CD19 and an anti-CD3 scFv which is effective in B cell malignancies (refer to abstract; pg 1242-1243; Fig. 2-4). Importantly, Wolf discloses that said technology may also be used in therapeutic areas beyond cancer, such as for the selective elimination of activated immune cell subpopulations in inflammatory lesions by redirected T cells (refer to abstract; pg 1242-1243; Fig. 2-4).
It would be obvious to one of the skill in the art to combine the teachings of Wolf and Gill to reach the instant fusion protein with a reasonable expectation of success using routine modifications.
Wolf teaches that CD3-BiTE molecules have an ability to induce target cell elimination by unstimulated
peripheral T cells without the need for extra T cell co-stimuli or T cell pre-activation regimens (see e.g. page 1239, left column). No simultaneous administration of co-stimulatory reagents is needed; therefore, BiTE development is simpler than for other bispecific antibodies (see e.g. page 1243, right column). Further, Wolf anticipate that the selective elimination of activated immune cell subpopulations
in inflammatory lesions by redirected T cells would provide a new therapeutic application beyond cancer (see e.g. paragraph 1243, right column). Combining the CAAR of Gill with the anti-CD3 BiTE of Wolf would create a molecule capable of specifically targeting cells that are directly involved in immune-mediated diseases such as membranous nephropathy (see e.g. Gill, page 1, lines 10-15), by targeting the immune cells that express autoantibodies to autoantigens such as PLA2R (see e.g. Gill, page 1, lines 23-27). The skilled artisan would be motivated to do so, as there is an unmet clinical need to provide better therapeutics for the treatment of membranous nephropathy which specifically target the autoimmune reactive immune cells.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claim(s) 1-4, 6, 8-12 and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gill et al (CA 3098865A1; filed 5/2/19; published 11/7/19) in view of Wolf et al ("BiTEs: bispecific antibody constructs with unique anti-tumor activity", DRUG DISCOVERY TODAY, vol. 10, no. 18, 15 September 2005, pages 1237-1244) and further in view of Bornhorst et al (Methods Enzymol. 2000 ; 326: 245–254).
The instant claims are directed to a fusion protein comprising: an N-terminal fragment of the phospholipase A2 receptor (PLA2R) extracellular domain, and an antigen-binding fragment of an anti-CD3 antibody.
Instant claim 2 is directed to the fusion protein according to claim 1, wherein the N-terminal fragment of the PLA2R extracellular domain comprises the Cysteine-rich domain (CysR).
Instant claim 3 is directed to the fusion protein according to claim 2, wherein said CysR has an amino acid sequence of SEQ ID NO:1.
Instant claim 4 is directed to the fusion protein according to claim 2, wherein said N-terminal fragment of the PLA2R extracellular domain further comprises the single fibronectin type-2 domain (FnII) and from 1 to 7 C-type lectin-like domains (CTLD1-7).
Instant claim 5 is directed to the fusion protein according to claim 1, wherein said anti-CD3 antibody is blinatumomab or muromonab.
Instant claim 6 is directed to the fusion protein according to claim 1, wherein said antigen- binding fragment of an anti-CD3 antibody is scFv.
Instant claim 7 is directed to the fusion protein of claim 6, wherein said scFv is selected from SEQ ID NOs:2, 3, 4 and 5.
Instant claim 8 is directed to the fusion protein according to claim 1, further comprising a peptide linker interposed between the PLA2R extracellular domain and the anti-CD3 antigen-binding fragment.
Instant claim 9 is directed to the fusion protein according to claim 8, wherein said linker contains from 5 to 20 amino acid residues.
Instant claim 10 is directed to the fusion protein according to claim 9, wherein said linker comprises an amino acid sequence which is selected from (i) (Gly-Gly-Gly- Gly-Ser)n, wherein n = 1, 2, 3 or 4 (SEQ ID Nos:9, 10, 11 and 12, respectively) and (ii) (Gly)m, wherein m = 6, 7 or 8 (SEQ ID Nos 13, 14 and 15, respectively).
Instant claim 11 is directed to the fusion protein according to claim 1, which further comprises a purification tag.
Instant claim 12 is directed to the fusion protein according to claim 11, wherein said purification tag is a polyhistidine fragment.
Instant claim 15 is directed to a pharmaceutical composition comprising a fusion protein according to claim 1, a nucleic acid molecule encoding said fusion protein or an expression vector comprising said nucleic acid, together with pharmaceutically acceptable excipients.
Gill teaches a chimeric autoantibody receptor (CAAR) wherein the CAAR comprises a phospholipase A2 receptor (PLA2R) autoantigen or fragment thereof (see e.g. page 2, lines 9-12). The PLA2R can comprise an extracellular domain, a C-type lectin domain 1 and 2, and a fibronectin type II domain (see e.g. page 4, lines 5-23, and figure 2). The CysR domain can be encoded by SEQ ID NO:1, which is identical to instant SEQ ID NO:1 (see e.g. page 22, lines 22-30). Gill teaches a variety of suitable linkers, including a GS linker (see e.g. page 26, lines 4-6), which can have the sequence of GGGGSGGGGS (see e.g. page 28, lines 5-11). Gill teaches that the CAAR can be administered in a genetically modified T-cell (see e.g. page 3, lines 3-10). The cell can express and induce killing of B cells expressing autoantibodies (see e.g. page 5, line 30 to page 6, line 6)
Gill does not disclose a molecule with a CD3 antibody or scFv.
Wolf discloses bispecific T cell engager (BiTE) molecules that are bispecific single-chain antibodies for the polyclonal activation and redirection of cytotoxic T cells against pathogenic target cells (refer to abstract; pg 1242-1243; Fig. 2-4). Said molecules have outstanding therapeutic potential for the treatment of malignant diseases, for example, MT103 is a CD19-specific BiTE comprising an anti-CD19 and an anti-CD3 scFv which is effective in B cell malignancies (refer to abstract; pg 1242-1243; Fig. 2-4). Importantly, Wolf discloses that said technology may also be used in therapeutic areas beyond cancer, such as for the selective elimination of activated immune cell subpopulations in inflammatory lesions by redirected T cells (refer to abstract; pg 1242-1243; Fig. 2-4).
It would be obvious to one of the skill in the art to combine the teachings of Wolf and Gill to reach the instant fusion protein with a reasonable expectation of success using routine modifications.
Wolf teaches that CD3-BiTE molecules have an ability to induce target cell elimination by unstimulated
peripheral T cells without the need for extra T cell co-stimuli or T cell pre-activation regimens (see e.g. page 1239, left column). No simultaneous administration of co-stimulatory reagents is needed; therefore, BiTE development is simpler than for other bispecific antibodies (see e.g. page 1243, right column). Further, Wolf anticipate that the selective elimination of activated immune cell subpopulations
in inflammatory lesions by redirected T cells would provide a new therapeutic application beyond cancer (see e.g. paragraph 1243, right column). Combining the CAAR of Gill with the anti-CD3 BiTE of Wolf would create a molecule capable of specifically targeting cells that are directly involved in immune-mediated diseases such as membranous nephropathy (see e.g. Gill, page 1, lines 10-15), by targeting the immune cells that express autoantibodies to autoantigens such as PLA2R (see e.g. Gill, page 1, lines 23-27). The skilled artisan would be motivated to do so, as there is an unmet clinical need to provide better therapeutics for the treatment of membranous nephropathy which specifically target the autoimmune reactive immune cells.
Neither Gill nor Wolf teach a fusion protein with a polyhistidine tag for purification.
Bonhorst teaches use of polyhistidine tags to purify recombinant proteins based on a “widely employed method” utilizing immobilized metal-affinity chromatography (see e.g. abstract, page 1, first two paragraphs). In particular, IMAC can be used to rapidly purify polyhistidine affinity-tagged proteins (see e.g. abstract, page 1, first two paragraphs).
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to formulate the fusion protein of Gill in view of Wolf because affinity tags consisting of polyhistidine residues are commonly used for purification (see e.g. page 1, last two paragraphs). The tags can result in increased purity and allows for stringent washing steps (see e.g. page 1, last two paragraphs). Further, polyhistidine tags are small enough to be easily incorporated into any expression vector (see e.g. page 2, first full paragraph). The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The polyhistidine tag of Bornhorst presents a well-known variation in the art of purification that allows for rapid purification with a tag that can be introduced into recombinant proteins using conventional molecular biology techniques. It would have thus been predictable that the composition of Gill in view of Wolf could include a polyhistidine tag for purification, without alterations in the fusion protein function. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Conclusion
No claim is allowed.
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/ANDREA K MCCOLLUM/Examiner, Art Unit 1674
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