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 without traverse of Group I and species 1) receptor expressed on cell surface which is US28, 2) buffer which is bicarbonate buffer, 3) amino acid which is arginine, 4) growth factor or cytokine which is insulin, 5) further component which is serum albumin and 6) ex vivo matter which is lung, in the reply filed on 5/19/2026 is acknowledged.
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 deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). On p. 6, lines 24 and 31, p. 7, line 7, p.77, lines 1 and 22, “RQRR” or “ArgGlnArgArg” must be identified as SEQ ID NO:16. On p. 6, lines 24 and 30, p. 7, line 11, p. 77, lines 5 and 25, “RQPR” or “ArgGlnProArg” must be referred to by a unique sequence identifier or, for example, as amino acids 101-104 of SEQ ID NO:14.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, 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.
Drawings
The drawings are objected to because in Fig. 8, the top legend should have “1.7” instead of “1,7”. In Figures 7-12, “cyckloheximide” should be “cycloheximide”. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Information Disclosure Statement
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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See p. 10, line 21.
The disclosure is objected to because of the following informalities: On p. 30, lines 5 and 6, there should be period instead of a comma in “0,”. On p. 74, line 26, “CXC3R1” should be “CX3CR1”. In the Table bridging pp. 79-80, there should be a period instead of comma in the nM values.
Appropriate correction is required.
The use of the terms on p. 79, of companies Sandoz, Loe Pharma, Merck, and products Solu-Medrol and Primaxin, and on p. 40, line 12, Sarstedt (see also p. 82, lines 13-20), each of which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 12 is objected to because of the following informalities: in the second to last line after “lysine”, a word such as “and” should be added because it is not the lysine that does not include the remaining amino acids. 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 1-8, 12, 13, 16, 19, 20, 23, 28, 31-33 and 37 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a composition wherein the intended use or method of use is for inhibiting a latent or active viral infection and the receptor expressed on the cell is one bound by a virus, does not reasonably provide enablement for prevention or prophylaxis of a viral infection or treatment or prevention of any other pathogen infection. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The claims are drawn to a composition, wherein the intended use or method of use is for prevention or treatment by a pathogen in an ex vivo organ, tissue and/or stem cell culture prior to transplantation. The composition comprises a fusion protein comprising a peptide binding a cell surface receptor and a second part with a toxin and cleavage site which is ArgX1X2Arg, wherein X2 is Arg or Lys and comprises an aqueous medium as set forth in the claims. The disclosure is directed to antiviral treatment of organs, tissues or stem cells for transplantation. All the working examples are limited to antiviral treatment. The prior art supports antiviral treatment for transplanted living material. For example, Speiss et al. (Journal of Immunology Research (2017), cited in the IDS) taught a fusion protein comprising a first peptide comprising the F49A mutant of CX3CL1 and which has higher selectivity for the US28 cell surface receptor fused to the catalytic domain of Pseudomonas exotoxin A (Abstract). It is taught that once the target domain binds to its receptor, the immunotoxin is internalized by endocytosis, cleaved in domain II by the proprotein convertase furin, leading to the release of the toxin and subsequent cell killing (1st paragraph of the Introduction on 1st page). Receptor U28, a viral-encoded G protein-coupled receptor is encoded by human cytomegalovirus (HCMV) and is bound by human ligand CX3CL1 (paragraph bridging pp. 1-2). Instant SEQ ID NO:6 comprises as the first part of the fusion protein, a CX3CL1 protein fragment that can bind US28. Kotton et al. (Organ Transplantation, Risks. Reference Module Biomed. Sci. 2015: B978-0-12-801238-3.02629-5, 2015, Abstract) teaches that:
Viruses are among the most common causes of opportunistic infection after solid organ and hematopoietic stem cell transplantation (SOT and HSCT). Viral infection is associated with both direct (invasive disease) and indirect (immune modulation) effects affecting susceptibility to other infections and promoting allograft rejection. The transplantation recipient is susceptible to a broad array of viral pathogens.
While there is enablement for wherein the pathogen is a virus, there is not for a pathogen that is not a virus. There is no limitation in claim 1 about what the receptor(s) expressed on the cell is. Further, if the part of the fusion protein binding a cell surface receptor does not bind a receptor associated with viral infection, e.g., US28, the fusion protein can bind any cell receptor and kill that cell, which is not enabled because the skilled artisan would have found this highly undesirable and it could lead to serious negative physical effects, such as death (e.g., binding receptors on cardiac cells with subsequence cardiac cell killing).
Also, while there is enablement for treating a viral infection, including a latent viral infection, there is none for preventing a viral infection wherein the organ, tissue or stem cell has not been infected by a virus. This pertains to any intended use but also to the method of claim 37. The disclosed method relies on the fusion protein binding a viral receptor expressed by an infected cell. If no infection has occurred, the viral receptor will not have been expressed and the only cells to be killed will be those expressing a natural receptor to which the fusion protein binds, in the case of CX3CL1 the receptor is CX3CR1 (see Speiss et al., ibid., p. 2, section 2.2). The instant method includes infection in an ex vivo organ, tissue or stem cell culture prior to transplantation. The term “preventing” generally carries the meaning of keeping something from happening. There is no guidance for or working example of preventing an infection by the method of the instant claims. Because the invention is based on binding a cell surface receptor expressed by a virus, wherein the cell must necessarily be part of the organ, tissue or stem cell to be transplanted, the virus must be within the cell either as part of a latent or active infection. Therefore, with the fusion protein of the claims, one cannot prevent a viral infection that has not yet occurred.
Claims 1-8, 12, 13, 16, 19, 20, 23, 28, 31-33 and 37 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 claims are drawn to a composition, wherein the intended use or method of use is for prevention or treatment by a pathogen in an ex vivo organ, tissue and/or stem cell culture prior to transplantation. The composition comprises a fusion protein comprising a peptide binding a cell surface receptor and a second part with a toxin and cleavage site which is ArgX1X2Arg, wherein X2 is Arg or Lys and comprises an aqueous medium as set forth in the claims. The specification discloses the fusion protein of SEQ ID NO:6 comprising the cleavage site and toxin from Pseudomonas exotoxin (PE), as well as a US28 receptor binding region. A fusion protein meeting these structural limitations, i.e., having in order a first peptide that binds U28 and a second peptide that has a cleavage site of RXR/LR and toxin that is PE or Diphtheria toxin and a method of treating a viral infection in an ex vivo organ, tissue and/or stem cell culture prior to transplantation by contacting with the fusion protein in an aqueous composition meets the written description provision of 35 USC 112(a). However, the claims are directed to or encompass fusion proteins that bind any cell surface receptor, comprise any toxin, and are directed at any pathogen. None of these fusion proteins or methods of using meets the written description provision of 35 USC 112(a).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states 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).
The disclosure is directed to antiviral treatment of organs, tissues or stem cells for transplantation. All the working examples are limited to antiviral treatment. There is support for wherein the fusion protein of the composition comprises a toxin which is Pseudomonas exotoxin (PE) or Diphtheria toxin because Chiron et al. (J. Biol. Chem. 268(27):18167-18176, 1994, cited in the IDS, p. 18168, col. 1, first paragraph) teaches that both those toxins have a furin-cleavage site, which cleaves after RXKR or RXRR, consistent with the required cleavage site of the claims. All working examples used PE as the toxin. Because the fusion protein of the instant claims has a second peptide comprising a cleavage site having one of those two four-amino acid cleavage sequences and has a toxin, and the specification only discloses PE in the working examples and no other toxins that do not have one of these cleavage sequences as functional in the claimed composition, there is not sufficient written description for wherein the toxin portion of the fusion protein is not from PE or Diphtheria toxin.
Further, the specification has disclosed a single pathogen receptor, viral receptor US28, to which the fusion protein binds and would reasonably be expected, for claim 37, to have antiviral activity. “Human cytomegalovirus (HCMV) is a species-specific herpesvirus and a significant pathogen particularly in immunocompromised individuals, neonates and patients receiving a transplant. HCMV has a lifecycle consisting of a latent and a lytic phase and expresses a constitutively internalizing receptor, US28, in both phases.” (p. 1, lines 20-23) The specification further discloses (p. 9, lines 7-9), “The present inventors have generated a fusion protein that effectively targets and kills infected cells, such as CMV infected cells including latently infected cells, upon binding to a receptor, e.g. a receptor encoded by a virus, such as a US28,…” It is explained, “Thus, chemokines or other compounds that binds US28 are internalized into the cell that express the receptor. US28 is expressed on the surface of CMV infected cells lytically or latently infected with CMV.” It is disclosed that CX3CL1 binds US28 and therefore meets the limitations of the claims for a first peptide that binds at least one receptor expressed on a cell. The receptor is necessarily from a pathogen and the only pathogen receptor that a disclosed fusion protein has been shown to bind is from a virus. The prior art supports antiviral treatment for transplanted living material. For example, Speiss et al. (Journal of Immunology Research (2017), cited in the IDS) taught a fusion protein comprising a first peptide comprising the F49A mutant of CX3CL1 and which has higher selectivity for the US28 cell surface receptor and that is fused to the catalytic domain of PE (Abstract). Also, Speiss et al. (supra) taught that once the target domain binds to its receptor, the immunotoxin is internalized by endocytosis, cleaved in domain II by the proprotein convertase furin and leading to the release of the toxin and subsequent cell killing (1st paragraph of the Introduction on 1st page). The fusion must first bind a pathogen-infected cell and then allow the fused toxin to kill the cell. This is complex. The skilled artisan cannot readily envisage a representative number of fusion proteins meeting the limitations of the claims, including for the intended use set forth in claim 1. Applicant has not disclosed any relevant, identifying characteristics, such as structure or other physical and/or chemical properties, sufficient to show possession of the claimed genus. Mere idea or function is insufficient for written description; isolation and characterization at a minimum are required. A description of what a material does, rather than what it is, usually does not suffice. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
As discussed above, there is only sufficient written description for wherein the pathogen is a virus and the cell surface receptor is US28. Also, there is only support for wherein the infection is an active or latent infection and there is no support for preventing an infection. If no infection has occurred, the viral receptor will not have been expressed and the only cells to be killed will be those expressing a natural receptor to which the fusion protein binds, in the case of CX3CL1 the receptor is CX3CR1 (see Speiss et al., ibid., p. 2, section 2.2). This would be detrimental to the organ, tissue or stem cell. There is no description of prevention of an infection with the claimed fusion protein and it does not appear the inventors were in possession of a method of prevention as claimed.
With the exception of the fusion protein referred to above, the skilled artisan cannot envision the detailed chemical structure of the encompassed fusion proteins, 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 isolating it. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Therefore, for the composition and method only a fusion protein comprising in order a first peptide that binds US28 receptor and a second peptide comprising a RXRR or RXKR cleavage site and a PE or DT toxin, wherein the pathogen to be treated is a virus and the treatment is of a viral infection (active or latent), but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112(a). 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).
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.
Claim Rejections - 35 USC § 102
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 1-6, 8, 16, 32 and 33 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Speiss et al. (Journal of Immunology Research (2017), cited in the IDS) as evidenced by Chiron et al. (J. Biol. Chem. 268(27):18167-18176, 1994, cited in the IDS) and MilliporeSigma (https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/cell-culture-and-cell-culture-analysis/mammalian-cell-culture/dulbecco-modified-eagle-medium-formulation?srsltid=AfmBOorTOkHslkhFWV6P7wM8YemZqs3ORVh_RudDpv6TT6ZL5h50wMel, 2026).
Speiss et al. teaches a fusion-toxin protein (FTP) comprising a first peptide comprising the F49A mutant of CX3CL1 and which has higher selectivity for the US28 receptor fused to the catalytic domain of Pseudomonas exotoxin A (Abstract). It teaches once the target domain binds to its receptor, the immunotoxin is internalized by endocytosis, cleaved in domain II by the proprotein convertase furin, leading to the release of the toxin and subsequent cell killing (1st paragraph of the Introduction on 1st page). The fusion protein was in a composition comprising a PBS (phosphate buffered saline) buffer and added to cells comprising DMEM medium (p. 3, col. 2, and p. 2, section 2.1.1). The FTP killed cells infected by a virus (Fig. 1). It reasonably appears the FTP of Speiss et al. would have a sequence at least 80% identical to instant SEQ ID NO:6 in view of the structure of the FTP set forth in Fig. 5 of Speiss et al. compared to instant Fig. 1B. Fig. 1E of Speiss et al. shows the fusion protein of instant claim 1 and instant Fig. 1B, including comprising the F49A mutation in the receptor-binding region (instant fusion SYN002) that causes binding to U28 to be of significantly higher affinity than to CX3CR1 (p. 8430 col. 1, last two full paragraphs). It reasonably appears, absent evidence to the contrary, that Speiss et al. discloses the construct called SYN002 in the instant specification. As such, the fusion protein of Speiss et al. would inherently have the same functions of that of the instantly claimed fusion protein. Because the composition has the intended use of treating an infection by a pathogen in an ex vivo organ, tissue, and/or stem cell culture prior to transplantation, this could apply to any number of organs, such as liver of lungs and to preserving their viability prior to transplantation (claims 32 and 33). Speiss et al. is silent with respect to the sequence of the cleavage site.
Chiron et al. teaches that PE has an endogenous furin-cleavage site, which cleaves after RXKR or RXRR (p. 18168, col. 1, first paragraph). Chiron is not necessary for anticipation but provided only to show an inherent property of PE.
Millipore Sigma teaches the components of DMEM used by Speiss et al. as comprising inorganic salts including Magnesium Sulfate, Potassium Chloride, Sodium Bicarbonate, Sodium Chloride, Sodium Phosphate Monobasic, Calcium Chloride, and also glucose and vitamins
Note that according to MPEP § 2111.02(II): “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020)”
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.
Claim(s) 1-8, 12, 13, 16, 19, 20, 23, 28, 31-33 and 37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Speiss et al. (Journal of Immunology Research (2017), cited in the IDS) as evidenced by Chiron et al. (J. Biol. Chem. 268(27):18167-18176, 1994, cited in the IDS) and MilliporeSigma (https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/cell-culture-and-cell-culture-analysis/mammalian-cell-culture/dulbecco-modified-eagle-medium-formulation?srsltid=AfmBOorTOkHslkhFWV6P7wM8YemZqs3ORVh_RudDpv6TT6ZL5h50wMel, 2026) as applied to claims 1-6, 8, 16, 32 and 33 above, and further in view of US Patent 9,078,428 B2 (Hassanein, cited in the IDS), Southard et al. (Transplantation, 49(2):251-267, 1990), US Patent 10,300,029 B2 (Mangino), US Patent 9,834,755 B2 (Berstein) and Cypel (Operative Techniques Thoracic Cardiovascular Surg. 19:433-442, 2014) and Ravikumar et al. (Am. J. Transpl. 16:1779-1787, 2016), and as admitted in the instant application on p. 78, lines 31-35.
Speiss et al. teaches a fusion-toxin protein (FTP) comprising a first peptide comprising the F49A mutant of CX3CL1 and which has higher selectivity for the US28 receptor fused to the catalytic domain of Pseudomonas exotoxin A (Abstract). It teaches once the target domain binds to its receptor, the immunotoxin is internalized by endocytosis, cleaved in domain II by the proprotein convertase furin, leading to the release of the toxin and subsequent cell killing (1st paragraph of the Introduction on 1st page). The fusion protein was in a composition comprising a PBS (phosphate buffered saline) buffer and added to cells comprising DMEM medium (p. 3, col. 2, and p. 2, section 2.1.1). The FTP killed cells infected by a virus (Fig. 1). It reasonably appears the FTP of Speiss et al. would have a sequence at least 80% identical to instant SEQ ID NO:6 in view of the structure of the FTP set forth in Fig. 5 of Speiss et al. compared to instant Fig. 1B. Fig. 1E of Speiss et al. shows the fusion protein of instant claim 1 and instant Fig. 1B, including comprising the F49A mutation in the receptor-binding region (instant fusion SYN002) that causes binding to U28 to be of significantly higher affinity than to CX3CR1 (p. 8430 col. 1, last two full paragraphs). It reasonably appears, absent evidence to the contrary, that Speiss et al. discloses the construct called SYN002 in the instant specification. As such, the fusion protein of Speiss et al. would inherently have the same functions of that of the instantly claimed fusion protein. Speiss et al. teaches that the FTPs efficiently controlled HCMB infection in vitro with high potency (p. 2, col.1, end of third paragraph). Speiss et al. does not teach ex vivo treatment of an organ, tissue or stem cell culture to treat a viral infection thereof. Nor are particular aqueous compositions of the FTP taught other than PBS and DMEM.
Chiron et al. teaches that PE has an endogenous furin-cleavage site, which cleaves after RXKR or RXRR (p. 18168, col. 1, first paragraph). Chiron is not necessary for anticipation but provided only to show an inherent property of PE.
Millipore Sigma teaches the components of DMEM used by Speiss et al. as comprising inorganic salts including Magnesium Sulfate, Potassium Chloride, Sodium Bicarbonate, Sodium Chloride, Sodium Phosphate Monobasic, Calcium Chloride, and also glucose and vitamins.
In reference to specifically claims 1, 4-6, 8, 12-14 and 16, Hassanein teaches in claim 1 a composition comprising a buffering component (sodium bicarbonate, sodium chloride, potassium chloride), an amino acid (L-arginine, L-glutamic acid, L-leucine), a carbohydrate (dextrose, mannitol), a growth factor (insulin) and a further component (a vitamin, methylprednisolone sodium succinate, epinephrine [a cardiac stimulant]). The composition does not comprise asparagine, glutamine or cysteine. It does, however, comprise magnesium sulfate heptahydrate and sodium glycerophosphate. It comprises sodium, potassium, magnesium, calcium, glutamic acid, histidine, mannitol and tryptophan.
In reference to instant claim 19, Southard et al. teaches components of the UW® solution, which are those of the second section of instant claim 19 and are listed on p. 252, col. 2, paragraph 3 of Southard et al. The solution was used for perfusion of rabbit livers (ibid.). The solution was shown to be effective for relatively long-term organ preservation (p. 256, last paragraph). The ingredients are hydroxyethyl starch, Potassium lactobionate (a combination of potassium hydroxide and lactobionic acid), Potassium phosphate monobasic, Magnesium Sulfate (heptahydrate), Raffinose (pentahydrate), Adenosine, Allopurinol, Glutathione and Sodium Hydroxide.
In reference to instant claim 20, Mangino teaches a ex vivo organ protection solution, wherein the solution includes adenine, calcium chloride, dextrose, glutathione, HEPES, hydroxyethyl starch, magnesium gluconate, mannitol, potassium phosphate, ribose, sodium gluconate and sodium hydroxide (col. 17, lines 48-56).
In reference to instant claim 23, Bernstein teaches a human stem cell composition comprising serum-free medium, human IL-3, human IL-6, thrombopoietin, Flt-3 ligand and human stem cell factor (col. 130, lines 24-32, see also claim 6). The composition is used to expand stem cells ex vivo (e.g., col. 145, line 63, through col. 146, line 1).
In reference to instant claim 28, Cypel et al. teaches ex vivo lung perfusion (EVLP) for donor lungs prior to transplantation (Abstract). The perfusion system uses Steen Solution TM (XVIVO Perfusion) made for EVLP to which was added heparin, imipenem and methylprednisolone (p. 433, col. 2, first full paragraph).
The instant application defines STEEN Solution TM as a composition of human serum albumen, dextran 40 and physiological salt solution (p. 78, lines 31-35).
In reference to claim 31, Ravikumar et al. teaches perfusion of ex vivo liver for transplantation (e.g., Fig. 1), wherein the perfusion device is primed with red blood cells, colloid solution with added calcium gluconate and cefuroxime (p. 1781, col. 1, second paragraph). The infusion includes insulin, heparin and prostacyclin (p. 1781, col. 1, first paragraph). The perfusion system allows for normothermic perfusion, avoiding long periods of cold and resulting in ischemia for the donor organ.
It would have been obvious to the artisan of ordinary skill before the effective filing date of the invention to have had the fusion protein of Speiss et al. in any suitable aqueous pharmaceutical composition in order to treat an organ, tissue or stem cell culture intended for donation as taught by the prior art in order to reduce the chance of potential viral infection transfer to the recipient from the donor organ, tissue or cells. As the prior art taught pharmaceutical compositions for ex vivo organ, tissue and stem cell culture maintenance/survival, it would have been obvious to use the anti-viral FTP of Speiss et al. in such a composition for its anti-viral property in a method of immersing, perfusing, storing, conditioning and/or flushing the ex vivo organ, tissue and/or stem cell culture prior to transplantation.
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 1-8, 12, 13, 16, 19, 20, 23, 28, 31-33 and 37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 21 of U.S. Patent No. 12,611,440 B2 (‘440) in view of US Patent 9,078,428 B2 (Hassanein, cited in the IDS), Southard et al. (Transplantation, 49(2):251-267, 1990), US Patent 10,300,029 B2 (Mangino), US Patent 9,834,755 B2 (Berstein) and Cypel (Operative Techniques Thoracic Cardiovascular Surg. 19:433-442, 2014) in view of the definition set forth on p. 78 of the instant application, and Ravikumar et al. (Am. J. Transpl. 16:1779-1787, 2016).
The instant claims are drawn to a composition for treating an infection by a pathogen in an ex vivo organ tissue and/or stem cell culture prior to transplantation, wherein the composition comprises 1) a fusion protein comprising a first peptide that binds a cell surface receptor fused to a second peptide with a cleavage site having the sequence ArgX1X2Arg, where X2 is Arg or Lys and the second peptide comprises a toxin, and 2) an aqueous medium comprising one or more of a buffering component, an amino acid, a carbohydrate or a growth factor (claim 1). Claim 2 defines the fusion protein as having SEQ ID NO:6 or a sequence at least 60% identity thereto. Further claims relate to the fusion protein killing a pathogen, including wherein the pathogen is a virus, wherein the organ or tissue is a specific type, including liver or lung, as well as further features of the composition (claims 3, 32, 33, 4-8, 12, 13, 16, 19, 20, 23, 28, 31). Claim 37 is drawn to a method comprising immersing, perfusing, storing, conditioning and/or flushing the ex vivo organ, tissue and/or stem cell culture in the composition of claim 1.
The claims of US Patent ‘440 are drawn to the same fusion protein, wherein the cell surface receptor is US28, which the fusion protein of SEQ ID NO:6 inherently binds (claims 1-3). They also claim (claims 4-7) a pharmaceutical composition thereof and an anti-viral agent. Claim 20 is drawn to a method of ex vivo treatment of a CMV (viral) infection of a solid organ or a hematopoietic stem cell for transplantation, comprising contacting the organ or stem cell with the pharmaceutical composition. ‘440 does not claim specific components of the pharmaceutical composition aside from the fusion protein and anti-viral agent.
In reference to specifically claims 1, 4-6, 8, 12-14 and 16, Hassanein teaches in claim 1 a composition comprising a buffering component (sodium bicarbonate, sodium chloride, potassium chloride), an amino acid (L-arginine, L-glutamic acid, L-leucine), a carbohydrate (dextrose, mannitol), a growth factor (insulin) and a further component (a vitamin, methylprednisolone sodium succinate, epinephrine [a cardiac stimulant]). The composition does not comprise asparagine, glutamine or cysteine. It does, however, comprise magnesium sulfate heptahydrate and sodium glycerophosphate. It comprises sodium, potassium, magnesium, calcium, glutamic acid, histidine, mannitol and tryptophan.
In reference to instant claim 19, Southard et al. teaches components of the UW® solution, which are those of the second section of instant claim 19 and are listed on p. 252, col. 2, paragraph 3 of Southard et al. The solution was used for perfusion of rabbit livers (ibid.). The solution was shown to be effective for relatively long-term organ preservation (p. 256, last paragraph). The ingredients are hydroxyethyl starch, Potassium lactobionate (a combination of potassium hydroxide and lactobionic acid), Potassium phosphate monobasic, Magnesium Sulfate (heptahydrate), Raffinose (pentahydrate), Adenosine, Allopurinol, Glutathione and Sodium Hydroxide.
In reference to instant claim 20, Mangino teaches a ex vivo organ protection solution, wherein the solution includes adenine, calcium chloride, dextrose, glutathione, HEPES, hydroxyethyl starch, magnesium gluconate, mannitol, potassium phosphate, ribose, sodium gluconate and sodium hydroxide (col. 17, lines 48-56).
In reference to instant claim 23, Bernstein teaches a human stem cell composition comprising serum-free medium, human IL-3, human IL-6, thrombopoietin, Flt-3 ligand and human stem cell factor (col. 130, lines 24-32, see also claim 6). The composition is used to expand stem cells ex vivo (e.g., col. 145, line 63, through col. 146, line 1).
In reference to instant claim 28, Cypel et al. teaches ex vivo lung perfusion (EVLP) for donor lungs prior to transplantation (Abstract). The perfusion system uses Steen Solution TM (XVIVO Perfusion) made for EVLP to which was added heparin, imipenem and methylprednisolone (p. 433, col. 2, first full paragraph).
In reference to claim 31, Ravikumar et al. teaches perfusion of ex vivo liver for transplantation (e.g., Fig. 1), wherein the perfusion device is primed with red blood cells, colloid solution with added calcium gluconate and cefuroxime (p. 1781, col. 1, second paragraph). The infusion includes insulin, heparin and prostacyclin (p. 1781, col. 1, first paragraph). The perfusion system allows for normothermic perfusion, avoiding long periods of cold and resulting in ischemia for the donor organ.
Claims of Patent ‘440 and the instant applications are coextensive towards a fusion protein comprising: 1) a first peptide which binds to at least one receptor expressed on a cell, and 2) a second peptide comprising a cleavage site having an amino acid sequence ArgX1X2Arg, wherein X2 is Arg or Lys, and wherein the second peptide comprises a toxin. Instant claim 2 specifies the fusion has the sequence of SEQ ID NO:6 (see claim 1 of patent). Instant method claim 37 and patented method claims 80, 81 and 93 are coextensive.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
WO 2021/008840 A1, cited in the IDS, is by 2 of the three instant inventors, Kledal and Rosenkilde, published after the effective filing date of the instant application and is not available as prior art under 35 USC 102(a)(2) according to exception 102(b)(2)(A). It teaches the instant anti-viral fusion toxin proteins referred to as SYN000, -001, -003, and -004 (e.g., Fig. 8).
XVIVO Perfusion (https://www.xvivoperfusion.com/wp-content/uploads/2016/02/SDS-STEEN-Solution.pdf, 2016) teaches the ingredients of STEEN SolutionTM as human serum albumen, dextran 40 and physiological salt solution. This reference confirms the definition in the specification.
Bridge to Life Ltd Instructions for use (https://bridgetolife.com/wp-content/uploads/2021/09/4107-us-belzer-uw-cs-multi-size-ifu-032321.pdf, 03/23/2021) teaches sale of Belzer UW® Cold Storage Solution for isolated organ perfusion and maintenance of the organ from donor organ removal through transplantation into recipient (Intended Use). The ingredients are Pentafraction (a hydroxyethyl starch), Lactobionic Acid (as Lactone), Potassium Phosphate monobasic, Magnesium Sulfate heptahydrate, Raffinose pentahydrate, Adenosine, Allopurinol, Glutathione, Potassium Hydroxide and Sodium Hydroxide. As evidenced by the bag label for the bag containing the Belzer UW® composition, it was commercially available at least as early as 10/05/2020 (https://bridgetolife.com/wp-content/uploads/2020/11/4055-us-belzer-uw-cs-bottom-label-1l-100520.pdf, 10/05/2020). This reference is cumulative with Southard et al.(above).
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
August 19,2026
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