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
Applicant’s election without traverse of Group I (claims 1-7 and 12-20) in the reply filed on 07/31/2025 is acknowledged.
Status of Claims
Claims 1-7 and 12-20 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. However, the provisional application 61/372,181 filed 08/10/2010 does not disclose all of the subject matter disclosed in the instant application. Therefore, the U.S. effective filing date of all claims under examination is set at 08/09/2011 based on the CIP of 13/206,304 (filed 08/09/2011).
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/19/2022, 01/19/2022, 01/26/2024, 02/27/2024, 02/27/2024, 03/06/2024, 03/06/2024 are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiencies –
Amino acid sequences appearing in the drawings (Figure 6) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
The amino acid sequence “SIINFEKL”, for example on Pg. 7 and several other pages appearing as “TER119-SIINFEKL” and on Pg. 30 and several other pages appearing as ““10F7-SIINFEKL”, in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim objections
Claim 12 is objected to because of the following informalities:
Claim 12 appears to have a typographical error. The word “antigen” is missing in the fourth line where it should read “wherein said antigen is collagen II”.
Appropriate correction is required.
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.
Claims 2, 4, 15 and 16 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. In the instant case, the claims are inclusive of a genus of erythrocyte-binding moieties derived from a 10F7 clone. However, the written description in this case does not adequately set forth any species of 10F7 clone derived binding moieties by structure or function. The specification does not disclose, and the art does not teach, the genus of erythrocyte-binding moieties derived from a 10F7 clone as broadly encompassed in the claims.
In Paragraph [0086], the instant specification discloses that embodiments include scFv conjugated to a tolerogenic antigen to make a molecular fusion that induces tolerance and the 10F7 antibody domain may be used to create antibody-antigen constructs capable of binding human erythrocytes. The specification discloses embodiments of scFvs that have been made, include 10F7-SIINFEKL, 10F7-ChrA, 10F7-proinsulin, and 10F7-uricase (Paragraph [0087]. In Paragraph [00191], the instant specification discloses that to affinity mature the 10F7 scFv that binds to human glycophorin-A, the gene was commercially synthesized and obtained from DNA2.0 (Menlo Park, CA, USA). It also discloses affinity maturation using recombinant DNA techniques is performed on the 10F7 gene to obtain a library of mutants to enable screening for enhanced binding towards human erythrocytes (Paragraph [00193]). In Paragraph [00239], the specification discloses several erythrocyte binding antigen constructs that have been created include 10F7-SIINFEKL, 10F7-ChrA, 10F7-proinsulin, and 10F7-uricase. In Paragraph [00252], the specification discloses that an embodiment is the case wherein the scFv comprises some or all of 10F7, e.g., one or more of a light chain of 10F7 and/or a heavy chain of 10F7 and/or a higher affinity variant of a light chain of 10F7 and/or a heavy chain of 10F7. Paragraph [00252] also discloses that an embodiment is the composition wherein the erythrocyte-binding moiety is chosen from the group consisting of a peptide ligand, an antibody, an antibody fragment, and a single chain antigen binding domain (ScFv), e.g., all or a portion of 10F7. Therefore, the written description only reasonably conveys a single 10F7 scFv. A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common to that genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.”
The inventions at issue in Lilly were DNA constructs per se, the holdings of that case is also applicable to claims such as those at issue here. Further, disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product. See Ariad, 598 F.3d at 1354-55 (“Regardless whether the asserted claims recite a compound, Ariad still must describe some way of performing the claimed methods... the specification must demonstrate that Ariad possessed the claimed methods by sufficiently disclosing molecules capable of reducing NF-kB activity so as to ‘satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed.’”) (internal citation omitted); see also Univ. of Rochester v. G.D. Searle& Co., Inc., 358 F.3d916,918 (Fed.Cir.2004) (applying the same analysis to assess written description for claims to a “method for selectively inhibiting” a particular enzyme by administering a functionally defined compound, i.e., a “non-steroidal compound that selectively inhibits activity” of the gene product for that enzyme).
In regard to claims to a product defined by function, without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 at1568 USPQ2d at 1406 (“definition by function…does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
The instant specification fails to provide sufficient descriptive information, such as definitive structural features that are common to the genus. That is, the specification provides neither a representative number of erythrocyte-binding moieties derived from a 10F7 clone that encompass the genus nor does it provide a description of structural features that are common to the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus. “[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.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Further, in view of Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017) and the Office’s February 2018 memo clarifying written description guidance for claims drawn to antibodies, the 2008 Written Description Training Materials are outdated and should not be relied upon as reflecting the current state of law regarding 35 U.S.C. 112. Further, a “newly characterized antigen” test flouts basic legal principles of the written description requirement (Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017)). Adequate written description of a newly characterized antigen alone is not considered adequate written description of a claimed antibody to that newly characterized antigen. Where an antibody binds to an antigen tells one nothing about the structure of any other antibody. Also, see the Board’s decision in Appeal 2017-010877 (claims to “A monoclonal antibody that binds a conformational epitope formed by amino acids 42-66 of SEQ ID NO:1”).
The functional requirements of the claimed antibodies is the sort of wish list of properties which fails to satisfy the written description requirement because “antibodies with those properties have not been adequately described.” Centocor, 636 F.3d at 1352. The “claims merely recite a description of the problem to be solved while claiming all solutions to it and ….. cover any compound later actually invented and determined to fall within the claim’s functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”Ariad Pharmaceuticals, Inc. v. EliLilly and Co.,598 F.3d 1336, 1353 (Fed. Cir. 2010).
Since the disclosure fails to describe common attributes or characteristics that adequately identify members of the genus, and because the genus is highly variant, the disclosure of potentially one erythrocyte-binding moieties derived from a 10F7 clone i.e. a scFv of 10F7, is insufficient to describe the genus. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as broadly claimed.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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). As discussed above, even though Applicant may propose methods of screening for possible members of the genus, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus, and therefore conception is not achieved until reduction to practice has occurred, 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 of isolation. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. See Ariad, 94 USPQ2d at 1161; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
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.
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.
Claim(s) 1, 3, 6, 7, 12, 14, and 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Gjertsson et al. (Mol Ther 2009 Apr;17(4):632-40) in view of Muzykantov et al. (WO2009086552A1 Date of Publication 2009-07-09), Simpson et al. (Prenatal diagnosis 15.10 (1995): 907-912) and Miller et al. (Nat Rev Immunol (2007) 7(9):665- 677; supplied as a reference in the specification and IDS).
Gjertsson et al. teaches using lentiviral gene transfer in vivo to express the immunodominant epitope of collagen type II (CII) on major histocompatibility complex class II molecules (MHC II) in a mouse model of destructive arthritis in an effort to develop strategies that mediate tolerance to autoantigens related to rheumatoid arthritis (Abstract). They teach the sequence corresponding to amino acids 259–270 of CII was fused into the class II-associated invariant chain peptide (CLIP) position of the invariant chain to achieve efficient binding to MHC II (Abstract). They also teach that compared with controls, mice intravenously injected with lentiviral vectors encoding this epitope displayed significantly less frequent, less severe, and less destructive arthritis, decreased lymphocyte proliferation in response to restimulation with CII, and lower CII–specific antibody levels and the antigen-specific tolerance induction using lentiviral gene delivery can ameliorate arthritis (Abstract). They further teach that T cell autoreactivity in RA has been detected against a range of epitopes including collagen type II (Pg. 632 Column, second, Paragraph, spanning, Lines 1-3).
Therefore, Gjertsson et al. teaches a composition for immunomodulation to achieve antigen-specific tolerance, the composition comprising a lentiviral vector encoding peptides of the CII antigen to which tolerance is desired; wherein the CII antigen is associated with T cell autoreactivity in rheumatoid arthritis.
Gjertsson et al. does not specifically teach a composition for immunomodulation to achieve antigen-specific tolerance, the composition comprising an erythrocyte-binding moiety, wherein the erythrocyte-binding moiety has the ability to non-covalently, specifically bind an exterior erythrocyte surface in situ in blood, wherein the erythrocyte-binding moiety comprises an antibody, antibody fragment, or a single chain variable fragment (scFv), wherein the antigen to which tolerance is desired is recombinantly fused or chemically conjugated to the erythrocyte-binding moiety. However, these deficiencies are made up in the teachings of Muzykantov et al.
Muzykantov et al. teaches fusion proteins comprising a single chain antigen-binding domain (scFv) of a monoclonal antibody fused via a linker to a therapeutic agent, where the monoclonal antibody (scFv) binds to a binding site expressed on the surface of a red blood cell at a density greater than 5,000 copies per red blood cell (Abstract, lines 10-15 on page 8, and line 19 on page 13 to line 16 on page 14, in particular). They teach that the sequences, proteins, and fragments of the fusion proteins may be produced by recombinant production, chemical synthesis, or other synthetic means (Pg. 14 line 19-21). They also teach that the scFv of the fusion protein can bind any determinant expressed on the surface of a red blood cell, preferably a human red blood cell (RBC) in a sufficient density such as glycophorin A associated protein (GPA), and preferably the anti-GPA scFv an anti-human GPA antibody (Pg. 9 Lines 18-21, Pg. 10 Lines 1-2 and Lines 7-8). They further teach that the level of GPA expression in humans is ~106 copies per RBC across the population, thus the use of anti-GPA scFv in the fusion proteins provides a viable therapeutic composition due to its wider range of RBC loading (Pg. 10 Lines 8-10). Muzykantov et al. also teaches a fusion protein with the anti-GPA scFv portion linked to a therapeutic protein agent on the N-terminus (Pg. 18 Line 18). Muzykantov et al. further teaches that fusion proteins that bind to RBCs have prolonged half-lives in the circulation that is extended from minutes to days (Pg. 3 Lines 21-22).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making a composition that comprises a fusion protein comprising a therapeutic agent fused via a linker to an anti-glycophorin A erythrocyte-binding scFv taught by Muzykantov et al. to ameliorate rheumatoid arthritis wherein the therapeutic agent is a tolerogenic peptide antigenic region of collagen II of Gjertsson et al. as an alternative to the lentivirus delivery system taught by Gjertsson et al. for delivery of a peptide antigenic region of collagen II because Muzykantov et al. teaches that targeting of fusion proteins comprising a therapeutic agent to a red blood cell is advantageous for purposes of systemic delivery, and/or for delivery to the site of a pathological condition (Pg. 10 Lines 32-34) and that fusion proteins that bind to RBCs have prolonged half-lives in the circulation (Pg. 3 Lines 21-22). This is an example of (B) Simple substitution of one known element for another to obtain predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
In particular regards to claims 1 and 12, since the "erythrocyte-binding moiety" scFv of Muzykantov et al. is erythrocyte-specific, it would predictably bind CD45-negative and not CD45-positive cells upon administration to a human because it specifically binds erythrocytes, which are known to be CD45 negative as taught by Simpson et al. (Pg. 908, Column, second, Paragraph, third Section “CD45 negative selection”). Further, the cited references do not indicate that composition of the combined method would induce an inflammatory response in antigen-specific T cells.
In particular regards to claims 12 and 18, one would predictably expect an RBC-targeting fusion protein of the combined method that comprises an antigenic peptide of collagen A linked to an scFv that targets glycophorin A, with its greater half-life as taught by Muzykantov et al., would have increased residence time so as to have the properties of inducing greater proliferation of antigen-specific CD8+ T cells, as compared to the proliferation of antigen-specific CD8+ T cells induced by just the antigen alone with a comparably reduced half-life. In addition, one would also expect a reduction in the numbers of resident lymph node interferon-gamma, as compared to the number of resident lymph node from this combined method since targeting the antigenic peptide to erythrocytes (which are absent in lymph nodes) would direct the composition of the combined method away from the lymph nodes and hence would have a reductive effect on lymph node interferon-gamma compared to a free antigen/antigenic peptide. Further, one would also expect by performing the combined method, a reduction in the numbers of spleen cells expressing interferon-gamma, as compared to the number of spleen cells because Miller et al. teaches that antigens or antigenic peptides linked to surfaces of cells from donors allow the donor cells to be perceived by the host in a non-inflammatory (non-immunogenic) fashion in the spleen (Pg. 669 Column, first and second, Paragraph, spanning, and Pg. 670, Column, second, Paragraph, third). Moreover, the instant specification acknowledges these effects are expected due to prior art teachings such as Miller et al. (Pg. 106 Reference number 13).
Claim Rejections - 35 USC § 103
Claim(s) 1, 3, 6, 7, 12, 14 and 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Gjertsson et al. (Mol Ther 2009 Apr;17(4):632-40) in view of Muzykantov et al. (WO2009086552A1 Date of Publication 2009-07-09), Simpson et al. (Prenatal diagnosis 15.10 (1995): 907-912), Miller et al. (Nat Rev Immunol (2007) 7(9):665- 677; supplied as a reference in the specification and IDS), Rothlin et al. (Cell 131, 1124–1136, 2007) and Ferguson et al. (Immunological Reviews 241:77-88, 2011).
Gjertsson et al. teaches using lentiviral gene transfer in vivo to express the immunodominant epitope of collagen type II (CII) on major histocompatibility complex class II molecules (MHC II) in a mouse model of destructive arthritis in an effort to develop strategies that mediate tolerance to autoantigens related to rheumatoid arthritis (Abstract). They teach the sequence corresponding to amino acids 259–270 of CII was fused into the class II-associated invariant chain peptide (CLIP) position of the invariant chain to achieve efficient binding to MHC II (Abstract). They also teach that compared with controls, mice intravenously injected with lentiviral vectors encoding this epitope displayed significantly less frequent, less severe, and less destructive arthritis, decreased lymphocyte proliferation in response to restimulation with CII, and lower CII–specific antibody levels and the antigen-specific tolerance induction using lentiviral gene delivery can ameliorate arthritis (Abstract). They further teach that T cell autoreactivity in RA has been detected against a range of epitopes including collagen type II (CII) (Pg. 632 Column, second, Paragraph, spanning, Lines 1-3).
Therefore, Gjertsson et al. teaches a composition for immunomodulation to achieve antigen-specific tolerance, the composition comprising a lentiviral vector encoding peptides of the CII antigen to which tolerance is desired; wherein the CII antigen is associated with T cell autoreactivity in rheumatoid arthritis.
Gjertsson et al. does not specifically teach a composition for immunomodulation to achieve antigen-specific tolerance, the composition comprising an erythrocyte-binding moiety, wherein the erythrocyte-binding moiety has the ability to non-covalently, specifically bind an exterior erythrocyte surface in situ in blood, wherein the erythrocyte-binding moiety comprises an antibody, antibody fragment, or a single chain variable fragment (scFv), wherein the antigen to which tolerance is desired is recombinantly fused or chemically conjugated to the erythrocyte-binding moiety. However, these deficiencies are made up in the teachings of Muzykantov et al.
Muzykantov et al. teaches fusion proteins comprising a single chain antigen-binding domain (scFv) of a monoclonal antibody fused via a linker to a therapeutic agent, where the monoclonal antibody (scFv) binds to a binding site expressed on the surface of a red blood cell at a density greater than 5,000 copies per red blood cell (Abstract, lines 10-15 on page 8, and line 19 on page 13 to line 16 on page 14, in particular). They teach that the sequences, proteins, and fragments of the fusion proteins may be produced by recombinant production, chemical synthesis, or other synthetic means (Pg. 14 line 19-21). They also teach that the scFv of the fusion protein can bind any determinant expressed on the surface of a red blood cell, preferably a human red blood cell (RBC) in a sufficient density such as glycophorin A associated protein (GPA), and preferably the anti-GPA scFv an anti-human GPA antibody (Pg. 9 Lines 18-21, Pg. 10 Lines 1-2 and Lines 7-8). They further teach that the level of GPA expression in humans is ~106 copies per RBC across the population, thus the use of anti-GPA scFv in the fusion proteins provides a viable therapeutic composition due to its wider range of RBC loading (Pg. 10 Lines 8-10). Muzykantov et al. also teaches a fusion protein with the anti-GPA scFv portion linked to a therapeutic protein agent on the N-terminus (Pg. 18 Line 18). Muzykantov et al. further teaches that fusion proteins that bind to RBCs have prolonged half-lives in the circulation that is extended from minutes to days (Pg. 3 Lines 21-22).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making a composition that comprises a fusion protein comprising a therapeutic agent fused via a linker to an anti-glycophorin A erythrocyte-binding scFv taught by Muzykantov et al. to ameliorate rheumatoid arthritis wherein the therapeutic agent is a tolerogenic peptide antigenic region of collagen II of Gjertsson et al. as an alternative to the lentivirus delivery system taught by Gjertsson et al. for delivery of a peptide antigenic region of collagen II because Muzykantov et al. teaches that targeting of fusion proteins comprising a therapeutic agent to a red blood cell is advantageous for purposes of systemic delivery, and/or for delivery to the site of a pathological condition (Pg. 10 Lines 32-34) and that fusion proteins that bind to RBCs have prolonged half-lives in the circulation (Pg. 3 Lines 21-22). This is an example of (B) Simple substitution of one known element for another to obtain predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
In particular regards to claims 1 and 12, since the "erythrocyte-binding moiety" scFv of Muzykantov et al. is erythrocyte-specific, it would predictably bind CD45-negative and not CD45-positive cells upon administration to a human because it specifically binds erythrocytes, which are known to be CD45 negative as taught by Simpson et al. (Pg. 908, Column, second, Paragraph, third Section “CD45 negative selection”). Further, prior art evidence maintains that antigen displayed in a physiological noninflammatory manner by apoptotic cells (such as erythrocytes which undergo an apoptosis-like process daily) to antigen-presenting cells (APCs) fail to induce a productive immune response, because Toll-like receptor signaling is inhibited by apoptotic cells (Rothlin et al. Pg. 1133 Column, second, Paragraph second, Lines 6-11), leading to antigen-specific T-cell deletion or anergy (Ferguson et al. Pg. 80 Fig 2). Therefore, the composition of the combined method would not be expected to induce an inflammatory response in antigen-specific T cells.
In particular regards to claims 12 and 18, one would predictably expect an RBC-targeting fusion protein of the combined method that comprises an antigenic peptide of collagen A linked to an scFv that targets glycophorin A, with its greater half-life as taught by Muzykantov et al., would have increased residence time so as to have the properties of inducing greater proliferation of antigen-specific CD8+ T cells, as compared to the proliferation of antigen-specific CD8+ T cells induced by just the antigen alone with a comparably reduced half-life. In addition, one would also expect a reduction in the numbers of resident lymph node interferon-gamma, as compared to the number of resident lymph node from this combined method since targeting the antigenic peptide to erythrocytes (which are absent in lymph nodes) would direct the composition of the combined method away from the lymph nodes and hence would have a reductive effect on lymph node interferon-gamma compared to a free antigen/antigenic peptide. Further, one would also expect by performing the combined method, a reduction in the numbers of spleen cells expressing interferon-gamma, as compared to the number of spleen cells because Miller et al. teaches that antigens or antigenic peptides linked to surfaces of cells from donors allow the donor cells to be perceived by the host in a non-inflammatory (non-immunogenic) fashion in the spleen (Pg. 669 Column, first and second, Paragraph, spanning, and Pg. 670, Column, second, Paragraph, third). Moreover, the instant specification acknowledges these effects are expected due to prior art teachings such as Miller et al. (Pg. 106 Reference number 13).
Claim Rejections - 35 USC § 103
Claim(s) 1-7 and 12-20 are rejected under 35 U.S.C. 103 as being unpatentable over Gjertsson et al. (Mol Ther 2009 Apr;17(4):632-40), Muzykantov et al. (WO2009086552A1 Date of Publication 2009-07-09), Simpson et al. (Prenatal diagnosis 15.10 (1995): 907-912) and Miller et al. (Nat Rev Immunol (2007) 7(9):665- 677) as applied to Claim(s) 1, 3, 6, 7, 12, 14, and 16-20 above and further in view of Taylor et al. (Protein Eng Des Sel. 2010 Apr;23(4):251-60) and Levin and Weiss (Mol BioSyst 2006, 2: 49-57).
The combined teachings of Gjertsson et al., Muzykantov et al., Simpson et al. and Miller et al. render obvious instant claims 1, 3, 6, 7, 12, 14, 16-20 as discussed above.
They do not teach the composition of claim 1, wherein the erythrocyte-binding moiety is derived from a 10F7 clone. They also do not teach the composition of claim 3, wherein the erythrocyte-binding moiety is derived from a 10F7 clone; or wherein the antibody fragment is affinity matured. They further do not teach the composition of claim 12, wherein the erythrocyte-binding moiety has the ability to bind Band 3 (CD233), glycophorin-A, glycophorin B (CD235b), glycophorin C(CD235c), or glycophorin D (CD235d) with an affinity generating a dissociation constant of between about 10 µM and 0.1 nM as determined by equilibrium binding measurements between the erythrocyte-binding moiety and erythrocytes; or wherein the erythrocyte-binding moiety is derived from a 10F7 clone, and wherein the erythrocyte-binding moiety is affinity-matured. However, these deficiencies are made up in the teachings below.
Taylor et al. teaches a single-chain variable fragment (scFv)-Epo fusion protein that used the anti-glycophorin A antibody, 10F7, as the scFv linked to Epo at the amino-terminal (Abstract and Pg. 250 Column, first, Paragraph, second). Taylor et al. also teaches that the Kd of 10F7/glycophorin interaction is roughly 100 nM, so an estimated 98% of a 10F7 scFv-Epo fusion protein is expected to be bound to mature red blood cells in a reversibly inactive state (Pg. 252, Column, second, Paragraph, second).
Levin and Weiss teach that affinity maturation of receptor–ligand interactions represents an important area of research that allows for improving affinity and specificity of proteins to tailor potency for in vivo and in vitro applications and a number of different display platforms including phage display, bacterial and yeast display, ribosome display, and mRNA display can optimize protein affinity and specificity (Abstract). They teach that affinity maturation of a humanized scFv against carcinoembryonic antigen, hMFE, improved its retention time in tumor tissue wherein hMFE variants with a large range of improved off rates (10 to 1000-fold) were obtained (Pg. 54 Column, first, Paragraph, second). They also teach that a second round of affinity maturation of the tightest binding variant was performed for enhanced stability by selecting for improved display levels on yeast resulting in the highest affinity-matured hMFE variant retaining 80% binding activity after incubation at 37⁰C for 9 days (Pg. 54 Column, first, Paragraph, second).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein the anti-glycophorin A erythrocyte-binding scFv is the 10F7 anti-glycophorin A scFv as taught by Taylor et al. or an erythrocyte-binding moiety that has been affinity matured as taught by Levin and Weiss because Taylor et al. teaches that a 10F7 scFv antibody fusion protein is a useful targeting element specific towards red blood cell lineage (Pg. 252, Column, first, Paragraph, spanning), and Levin and Weiss et al. teaches affinity maturation can that produce high affinity proteins with specific functions for use as therapeutic agents (Pg. 49, Column, first, Paragraph, first). This is an example of (B) Simple substitution of one known element for another to obtain predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Taken all together, the combination of art above clearly renders the claimed inventions above as a whole prima facie obvious.
Claim Rejections - 35 USC § 103
Claim(s) 1-7 and 12-20 are rejected under 35 U.S.C. 103 as being unpatentable over Gjertsson et al. (Mol Ther 2009 Apr;17(4):632-40), Muzykantov et al. (WO2009086552A1 Date of Publication 2009-07-09), Simpson et al. (Prenatal diagnosis 15.10 (1995): 907-912), Miller et al. (Nat Rev Immunol (2007) 7(9):665- 677), Rothlin et al. (Cell 131, 1124–1136, 2007) and Ferguson et al. (Immunological Reviews 241:77-88, 2011), as applied to Claim(s) 1, 3, 6, 7, 12, 14 and 16- 20 above and further in view of Taylor et al. (Protein Eng Des Sel. 2010 Apr;23(4):251-60) and Levin and Weiss (Mol BioSyst 2006, 2: 49-57).
The combined teachings of Gjertsson et al., Muzykantov et al., Simpson et al., Miller et al., Rothlin et al. and Ferguson et al. render obvious instant claims 1, 3, 6, 7, 12, 14, and 16-20 as discussed above.
They do not teach the composition of claim 1, wherein the erythrocyte-binding moiety is derived from a 10F7 clone. They also do not teach the composition of claim 3, wherein the erythrocyte-binding moiety is derived from a 10F7 clone; or wherein the antibody fragment is affinity matured. They further do not teach the composition of claim 12, wherein the erythrocyte-binding moiety has the ability to bind Band 3 (CD233), glycophorin-A, glycophorin B (CD235b), glycophorin C(CD235c), or glycophorin D (CD235d) with an affinity generating a dissociation constant of between about 10 µM and 0.1 nM as determined by equilibrium binding measurements between the erythrocyte-binding moiety and erythrocytes; or wherein the erythrocyte-binding moiety is derived from a 10F7 clone, and wherein the erythrocyte-binding moiety is affinity-matured. However, these deficiencies are made up in the teachings below.
Taylor et al. teaches a single-chain variable fragment (scFv)-Epo fusion protein that used the anti-glycophorin A antibody, 10F7, as the scFv linked to Epo at the amino-terminal (Abstract and Pg. 250 Column, first, Paragraph, second). Taylor et al. also teaches that the Kd of 10F7/glycophorin interaction is roughly 100 nM, so an estimated 98% of a 10F7 scFv-Epo fusion protein is expected to be bound to mature red blood cells in a reversibly inactive state (Pg. 252, Column, second, Paragraph, second).
Levin and Weiss teach that affinity maturation of receptor–ligand interactions represents an important area of research that allows for improving affinity and specificity of proteins to tailor potency for in vivo and in vitro applications and a number of different display platforms including phage display, bacterial and yeast display, ribosome display, and mRNA display can optimize protein affinity and specificity (Abstract). They teach that affinity maturation of a humanized scFv against carcinoembryonic antigen, hMFE, improved its retention time in tumor tissue wherein hMFE variants with a large range of improved off rates (10 to 1000-fold) were obtained (Pg. 54 Column, first, Paragraph, second). They also teach that a second round of affinity maturation of the tightest binding variant was performed for enhanced stability by selecting for improved display levels on yeast resulting in the highest affinity-matured hMFE variant retaining 80% binding activity after incubation at 37⁰C for 9 days (Pg. 54 Column, first, Paragraph, second).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein the anti-glycophorin A erythrocyte-binding scFv is the 10F7 anti-glycophorin A scFv as taught by Taylor et al. or an erythrocyte-binding moiety that has been affinity matured as taught by Levin and Weiss because Taylor et al. teaches that a 10F7 scFv antibody fusion protein is a useful targeting element specific towards red blood cell lineage (Pg. 252, Column, first, Paragraph, spanning), and Levin and Weiss et al. teaches affinity maturation can that produce high affinity proteins with specific functions for use as therapeutic agents (Pg. 49, Column, first, Paragraph, first). This is an example of (B) Simple substitution of one known element for another to obtain predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Taken all together, the combination of art above clearly renders the claimed inventions above as a whole prima facie obvious.
Conclusion
No claims are allowed.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642