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 .
Response to Restriction
Applicant’s election without traverse of claims 1, 63-68,70-72, and 74-76 in the reply filed on 04/12/2026 is acknowledged. Applicant elected a fusion protein and instant claim 80 includes a pharmaceutical composition comprising the species of a fusion protein; therefore claim 80 part (i) is rejoined for prosecution.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/16/2024 and 03/26/2025 are in compliance with the provisions of 37 CFR 1.97. Sources Guidotti et al. and Lacorazza et al. on IDS 01/16/2024 are not included in the application contents; therefore, they have been lined through. Accordingly, the information disclosure is being considered by the examiner, except where lined through.
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.
Claim 75 is 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.
Claim 75 is rejected as indefinite for because ‘the lysosomal enzyme” lacks antecedent basis. For the purposes of examination, it will be interpreted as dependent from claim 65.
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.
Claim(s) 1, 63-65, 70, and 80 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stern et al. US 10265412 B2 in view of Bai et al., 2005, Recombinant granulocyte colony-stimulating factor-transferrin fusion protein as an oral myelopoietic agent, PNAS, pgs. 7293-7296.
Regarding claims 1, 63-65, and 70, Stern teaches a hormone-therapeutic protein conjugate that is able to cross the blood brain barrier for treating lysosomal storage diseases (abstract). Specifically, Stern teaches a chimeric protein where granulocyte colony stimulating factor (G-CSF) is covalently linked by a peptide linker (Column 7, lines 20-30) to a therapeutic enzyme, namely β-hexosaminidase A (HEXA) (Column 77, Claim 1). Stern also teaches that the composition can be administered orally (Column 19, lines 25-27). Regarding claim 63, Stern teaches that HEXA is mutated in Tay Sachs disease which leads to the degradation of the brain and spinal cord (Column 14, lines 20-33). Regarding claim 70, Stern teaches that a proteinaceous therapeutic agent, namely HEXA, comprising SEQ ID NO: 26, which has 99.9% sequence identity to instant SEQ ID NO: 1 (see below) and is an active fragment thereof of instant SEQ ID NO: 1. Stern teaches that transferrin is also a blood brain barrier (BBB) targeting agent known in the art (Column 2, lines 25-35). Regarding claim 80, Stern et al. teaches a pharmaceutical composition comprising a chimeric protein comprising G-CSF and β-hexosaminidase A (Column 78).
Regarding Claim 1, Stern does not explicitly teach an embodiment where the fusion protein has two BBB targeting domains, namely a transferrin receptor binding peptide and G-CSF, which are then linked to a therapeutic agent.
Bai et al. teaches a fusion protein consisting of human G-CSF and human transferrin (Tf) protein (hereafter G-CSF-Tf). In other words, Bai et al. teaches a fusion of two BBB targeting agents, but without a therapeutic enzyme attached. Bai et al., teaches that when administered subcutaneously to mice, G-CSF-Tf had a similar therapeutic effect to G-CSF alone. Furthermore, Bai et al. teaches that when administered orally, the G-CSF-Tf protein had a sustained effect on myelopoiesis, while G-CSF alone had no effect (abstract). Bai et al. states that these findings provide an approach for future development of orally efficacious protein drugs (pg. 7295, right side, last paragraph).
It would be obvious to one of ordinary skill in the art to modify the G-CSF-linker-HEXA fusion protein, wherein HEXA is comprised of SEQ ID NO: 26 (which is an active fragment of instant SEQ ID NO: 1) of Stern et al. to include another BBB targeting protein, transferrin of Bai et al., to arrive at a fusion protein comprising G-CSF, transferrin targeting protein, and HEXA, wherein HEXA is an active fragment of SEQ ID NO: 1.Stern teaches that both G-CSF and the transferrin are known in the art as targeting agents that enable therapeutic agents to cross the blood brain barrier, but does not teach that a fusion protein that comprises both of them. Bai et al. teaches that a two domain protein comprising both G-CSF and a transferrin receptor binding peptide makes it a more effective in oral administration and just as effective in subcutaneous administration. The two sources are in the same field of endeavor, namely fusion proteins. One of ordinary skill in the art would be motivated to form a fusion protein comprising G-CSF, transferrin targeting protein, and HEXA, in order to enhance the efficacy of Stern’s composition for oral administration, which is particularly desirable because it is more accessible for patient populations compared to other administration methods such as subcutaneous or intravenous administration. One of ordinary skill in the art would have a reasonable expectation of success because 1) both of these targeting agents were known in the art to be effective for crossing the blood brain barrier alone, and 2) the combination of both targeting agents was functionally equivalent, if not more effective compared to G-CSF alone, as taught by Bai et al..
Instant SEQ ID NO: 1 with SEQ ID NO: 26 of Stern et al.:
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Claim(s) 66-67 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stern et al. US 10265412 B2, in view of Bai et al., as applied to claim 1 above, and further in view of Boado et al. (Genetic engineering, expression, and activity of a fusion protein of a human neurotrophin and a molecular Trojan horse for delivery across the human blood-brain barrier, 2007, Biotechnol Bioeng, pgs. 1376-1385 (see instant PTO-892).
The modified composition of Stern et al. and Bai et al. teach a fusion protein comprising G-CSF and transferrin targeting protein, attached to HEXA via a peptide linker, wherein HEXA is comprised of SEQ ID NO: 26 (which is an active fragment of instant SEQ ID NO: 1).The teachings of over Stern et al., in view of Bai et al., as applied to claim 1, are addressed above.
The modified composition of Stern et al. and Bai et al. does not teach that the proteinaceous therapeutic agent is brain derived neurotrophic factor (BDNF).
Boada et al. teaches that BDNF produces neurogenesis but can’t cross the blood brain barrier (pg. 1377, right side, first paragraph). Boado et al. teaches a fusion protein in which human BDNF is fused to the heavy chain of a chimeric antibody for the human insulin receptor (HIR) (hereafter HIRMAb-BDNF) (abstract, Fig. 2). Boado et al. teaches that HIRMAb-BDNF retained its functionality for the HIR and the receptor for BDNF. Boado et al. teaches that therapeutic levels of BDNF were produced in a primate brain after intravenous administration of the fusion protein (abstract). Boado et al. teaches that this therapy is useful for a variety of chronic and acute brain conditions such as acute ischemic stroke (pg. 1386, left side, first paragraph).
It would be obvious to one of ordinary skill in the art to substitute the HEXA of the fusion protein comprising G-CSF, transferrin targeting protein, and HEXA, wherein HEXA comprises SEQ ID NO: 26 (which is an active fragment of instant SEQ ID NO: 1) of modified Stern et al. and Bai et al. with BDNF to arrive at a fusion protein comprising G-CSF and transferrin targeting protein linked to BDNF via a peptide linker in order to generate a therapeutic agent to treat stroke. Stern et al. specifically mentions stroke as an ailment that is compatible with this treatment strategy (Column, left side, first two sentences) and Boada et al. teaches a BDNF fusion protein for treating stroke. One of ordinary skill in the art would have a reasonable expectation of success to generate a fusion protein comprising G-CSF, transferrin targeting protein, and BDNF that can be used to treat stroke as taught by Boado et al..
Claim(s) 68 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stern et al. US 10265412 B2, in view of Bai et al., as applied to claim 1 above, and further in view of Xiong et al. (Mature brain-derived neurotrophic factor and its receptor TrkB are upregulated in human glioma tissues, 2015, Oncology letters, pgs. 223-227 (see instant PTO-892).
The modified composition of Stern et al. and Bai et al. teach a fusion protein comprising G-CSF and transferrin targeting protein, attached to HEXA via a peptide linker, wherein HEXA is comprised of SEQ ID NO: 26 (which is an active fragment of instant SEQ ID NO: 1). The teachings of Stern et al., in view of Bai et al., as applied to claim 1, are addressed above.
The modified composition of Stern et al. and Bai et al. does not teach that the proteinaceous therapeutic agent is an antibody.
Xiong et al. teaches that gliomas express BDNF (abstract) and that expression of mature BDNF is positively associated with glioma malignancy grade and poor prognosis in nervous system tumors (pg. 223, right side, first four lines). Xiong et al. suggests BDNF neutralizing antibodies or TrkB-receptor antibodies as a treatment for glioma (pg. 226, left side, last 5 lines).
It would be obvious to one of ordinary skill in the art to substitute HEXA of the fusion protein comprising G-CSF, transferrin targeting protein, and HEXA, wherein HEXA comprises SEQ ID NO: 26 (which is an active fragment of instant SEQ ID NO: 1) of modified Stern et al. and Bai et al. with a BDNF neutralizing antibody as taught by Xiong et al. to arrive at a fusion protein comprising G-CSF and transferrin targeting protein linked to a BDNF neutralizing antibody via a peptide linker to treat glioma. Xiong specifically suggests BDNF neutralizing antibodies as a therapeutic option for glioma. There would be a reasonable expectation of success substituting HEXA to a BDNF neutralizing antibody because 1) Xiong et al. teaches that suppression of mature BDNF signaling pathway would be beneficial in treating glioma and 2) the targeting agents G-CSF and transferrin of modified Stern et al. and Bai et al. would ensure functional crossing of the blood brain barrier.
Claim(s) 71 and 75 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stern et al. US 10265412 B2, in view of Bai et al., as applied to claim 1 above, and further in view of Shoshan-Barmatz US 20160176937 A1 (see instant PTO-892).
The modified composition of Stern et al. and Bai et al. teach a fusion protein comprising G-CSF and transferrin targeting protein, attached to HEXA via a peptide linker, wherein HEXA is comprised of SEQ ID NO: 26 (which is an active fragment of instant SEQ ID NO: 1).The teachings of over Stern et al., in view of Bai et al., as applied to claim 1, are addressed above.
The modified composition of Stern et al. and Bai et al. does not teach that the transferrin receptor peptide sequence is the same as instant SEQ ID NO: 36.
Shoshan-Barmatz et al. teaches a conjugate peptide that comprises a transferrin receptor peptide which enhances cell permeability of an N-terminal domain of the human mitochondrial protein voltage-dependent anion channel 1 (VDAC). Shoshan-Barmatz et al. teaches that transferrin can transport large molecules and has low toxicity and high yield. Shoshan-Barmatz et al. teaches that the transferrin domain peptide SEQ ID NO: 15 has 76.9% sequence identity to instant SEQ ID NO: 36 (see below), which is an active analog thereof of instant SEQ ID NO: 36.
It would be obvious to one of ordinary skill in the art to modify the transferrin targeting protein of the modified fusion protein comprising G-CSF, transferrin targeting protein, and HEXA, wherein HEXA comprises SEQ ID NO: 26 (which is an active fragment of instant SEQ ID NO: 1) of Stern et al. and Bai et al. with SEQ ID NO: 15 of Shoshan-Barmatz et al., which is an active analog of instant SEQ ID NO: 36. These sources are all in the same field of endeavor, namely therapeutic conjugate proteins. One of ordinary skill in the art would have been motivated to combine these sources because Stern et al. teaches transferrin receptor mediated transport as a method of BBB transport (Column 9, lines 21-31). One of ordinary skill in the art would have a reasonable expectation of success using a fusion protein comprising G-CSF, HEXA, wherein HEXA comprises SEQ ID NO: 26 (which is an active fragment of instant SEQ ID NO: 1), and a transferrin targeting protein, wherein the transferrin protein comprises SEQ ID NO: 15 based on the successful results of the Tf peptide comprising SEQ ID NO: 15 in the carrier fusion protein taught by Shoshan-Barmatz et al..
Instant SEQ ID NO: 36 with SEQ ID NO: 15 of Shoshan-Barmatz:
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Claim(s) 72 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stern et al. US 10265412 B2, in view of Bai et al., as applied to claim 1 above, and further in view of Besman et al. US 8,129,348 B2 (see instant PTO-892).
The modified composition of Stern et al. and Bai et al. teach a fusion protein comprising G-CSF and transferrin targeting protein, attached to HEXA via a peptide linker, wherein HEXA is comprised of SEQ ID NO: 26 (which is an active fragment of instant SEQ ID NO: 1).The teachings of over Stern et al., in view of Bai et al., as applied to claim 1, are addressed above.
The modified composition of Stern et al. and Bai et al. does not teach that G-CSF has a sequence identical to instant SEQ ID NO: 11.
Besman et al. teaches SEQ ID NO: 2450, which is a biologically active protein conjugate with G-CSF which has the same sequence as instant SEQ ID NO: 11 (see below). Besman et al. teaches that the conjugate has an increased plasma half-life compared to the biological version of the protein (Column 141, lines 15-20).
It would be obvious to one of ordinary skill in the art to modify the G-CSF peptide of the modified fusion protein comprising G-CSF, transferrin targeting protein, and HEXA, wherein HEXA comprises SEQ ID NO: 26 (which is an active fragment of instant SEQ ID NO: 1) of Stern et al. and Bai et al. with SEQ ID NO: 2450 of Besman et al., which is identical to instant SEQ ID NO: 11.One of ordinary skill in the art would have been motivated to use the sequence taught by Besman et al. because the phosphatase leader sequence enables secretion of G-CSF without amino-terminal modification (Column 15, lines 1-6 and 23-35). Furthermore, both sources are in the same field of endeavor, namely therapeutic protein conjugates. One of ordinary skill in the art would have a reasonable expectation of success of forming a fusion protein comprising, G-CSF, wherein G-CSF comprises SEQ ID NO: 2450 (which is identical to instant SEQ ID NO: 11), transferrin targeting protein, and HEXA, wherein HEXA comprises the SEQ ID NO: 26 (which is an active fragment of instant SEQ ID NO: 1), because Besman et al. teaches the half-life of G-CSF can be successfully increased when coupled to a peptide motif, namely the phosphatase leader sequence, and an increased plasma half-life is desirable for therapeutic success (Column 5, lines 25-35).
Instant SEQ ID NO: 11 with SEQ ID NO: 2450 of Besman et al.:
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Claim(s) 74 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stern et al. US 10265412 B2, in view of Bai et al., as applied to claim 1 above, and further in view of Ceballos-Alcantarilla et al., (Chapter One - Understanding and applications of Ser/Gly linkers in protein engineering, 2020, Methods of Enzymology, pgs. .1-20) (see instant PTO-892).
The modified composition of Stern et al. and Bai et al. teach a fusion protein comprising G-CSF and transferrin targeting protein, attached to HEXA via a peptide linker, wherein HEXA is comprised of SEQ ID NO: 26 (which is an active fragment of instant SEQ ID NO: 1).The teachings of over Stern et al., in view of Bai et al., as applied to claim 1, are addressed above.
The modified composition of Stern et al. and Bai et al. does not explicitly teach that the peptide linker comprises Gly-Gly-Ser repeats.
Ceballos-Alcantarilla et al. teaches “Repeats of glycine and serine residues represent the most commonly used type of linker to construct multidomain fusion proteins” (pg. 2, second paragraph). Ceballos-Alcantarilla et al. teaches that these linkers do not affect the main protein domains or hamper their folding (pg. 3, first paragraph). Ceballos-Alcantarilla et al. teaches a peptide with Gly-Gly-Ser repeats (pg. 10, second paragraph; Table 1).
It would be obvious to modify the peptide linker of the modified fusion protein comprising G-CSF, transferrin targeting protein, and HEXA, wherein HEXA comprises SEQ ID NO: 26 (which is an active fragment of instant SEQ ID NO: 1) of Stern et al. and Bai et al. with a (Gly-Gly-Ser)2 linker. One of ordinary skill in the art would be motivated to do so because Stern et al. specifically suggests a peptide linker that may promote protein folding (Column 7, lines 26-30) and Ser/Gly linkers, as taught by Ceballos-Alcantarilla et al., are flexible. One of ordinary skill in the art would have a reasonable expectation of success of forming a fusion protein comprising G-CSF, transferrin targeting protein, and HEXA connected via a (Gly-Gly-Ser)2 linker because Ser/Gyl linkers are the conventional linker for fusion proteins, as taught by Ceballos-Alcantarilla et al.
Claim(s) 76 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stern et al. US 10265412 B2, in view of Bai et al., and in further view of Boada et al., as applied to claim 66 above, in further view of Shoshan-Barmatz et al., as applied to claim 71 above, further in view of Besman et al., as applied to claim 72 above, and in further view of Wang et al. US 7205387 B2 (hereafter Wang) (see instant PTO-892).
The modified composition of Stern et al., Bai et al., and Boada et al. teach a fusion protein comprising G-CSF and transferrin targeting protein, attached to BDNF via a peptide linker. As defined in the specification (pg. 19, lines 25-30), the term “G-CSF” includes G-CSF includes analogs and fragments.
The modified composition of Stern et al., Bai et al., and Boada et al. does not teach that the neurotrophic factor BDNF has a sequence of instant SEQ ID NO: 30. The modified composition of Stern et al., Bai et al., and Boada et al. does not teach that G-CSF has instant SEQ ID NO: 11 or that the transferrin receptor binding peptide is SEQ ID NO: 36.
Shoshan-Barmatz et al. teaches a transferrin receptor binding peptide SEQ ID NO: 15 which has 76.9% sequence identity to instant SEQ ID NO: 36, which is an active fragment thereof of instant SEQ ID NO: 36.. As defined in the specification (pg. 17, lines 25-30) transferrin receptor binding peptide encompasses active fragments.
Besman et al. teaches G-CSF with SEQ ID NO: 2450 which is identical to instant SEQ ID NO: 11, as discussed previously.
Wang et al. teaches SEQ ID NO: 2 is the human BDNF sequence (Column 2, lines 59-60) and is identical to instant SEQ ID NO: 30 (see below). Wang teaches an embodiment of a recombinant polypeptide that comprises a portion of SEQ ID NO: 2 to treat neurological disorders (abstract; Column 10, lines 34-45).
It would be obvious to modify BDNF, G-CSF, and the transferrin targeting protein of the fusion protein comprising G-CSF, transferrin targeting protein, and BDNF of modified Stern et al., Bai et al. and Boada et al. with the transferrin targeting protein comprising SEQ ID NO: 15 of Shoshan-Barmatz et al. (which is an active analog of instant SEQ ID NO: 36), G-CSF comprising SEQ ID NO: 2450 of Besman et al. (which is identical to SEQ ID NO: 11), and the BDNF comprising SEQ ID NO:2 (which is identical to instant SEQ ID NO: 30) of Wang et al., to arrive at the claimed invention. In other words, it would be obvious to use known sequences for transferrin, G-CSF, and BDNF for a fusion protein comprising these elements. All of these sources are in the same field of endeavor, namely therapeutic recombinant proteins. There would be a reasonable expectation of success using known peptides in the art for known components of the modified protein.
Instant SEQ ID NO: 30 with SEQ ID NO: 2 of Wang et al.:
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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, 63-65, and 80 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5 of U.S. Patent No. US 10265412 B2 (hereafter the reference patent) in view of Bai et al (see instant PTO-892).
Claim 1 of the reference patent teaches a chimeric protein for delivery of a therapeutic enzyme across the blood brain barrier comprising G-CSF covalently linked to β-hexosaminidase A (HEXA). Claim 3 of the reference patent teaches that the G-CSF is covalently linked via linking molecule. Claim five of the reference patent further teaches a pharmaceutical composition comprising the chimeric protein.
Regarding instant claim 1, the reference patent does not teach that the fusion protein is a two-domain carrier protein with both G-CSF and a transferrin receptor binding peptide.
The teachings of Bai et al. are described in detail above.Bai et al. teaches a fusion protein consisting of human G-CSF and human transferrin (Tf) protein, hereafter G-CSF-Tf.
It would be obvious to one of ordinary skill in the art to modify the G-CSF-linker-HEXA fusion protein of the reference patent to include another BBB targeting protein, transferrin of Bai et al., to arrive at a fusion protein comprising G-CSF, transferrin targeting protein, and HEXA.
Bai et al. teaches that the combination of both G-CSF and a transferrin receptor binding peptide makes it a more effective in oral administration and just as effective in subcutaneous administration. The two sources are in the same field of endeavor, namely fusion proteins. One of ordinary skill in the art would be motivated to combine these teachings in order to enhance the efficacy of the reference patent’s composition for oral administration, which is particularly desirable because it is more accessible for patient populations compared to other administration methods such as subcutaneous or intravenous administration. One of ordinary skill in the art would have a reasonable expectation of success because 1) both transferrin and G-CSF targeting agents were known in the art to be effective for crossing the blood brain barrier alone, and 2) the combination of both targeting agents was functionally equivalent, if not more effective compared to G-CSF alone, as taught by Bai et al..
Claim 70 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. US 10265412 B2 (hereafter the reference patent) in view of Bai et al., as applied to instant claim 1 and 65 above, in further view of US 2010/0183577 A1 (hereafter Stern II) (see instant PTO-892).
The modified composition of reference patent and Bai et al. teach a fusion protein comprising G-CSF, transferrin, and HEXA.
The modified composition of the reference patent and Bai et al. does not explicitly teach that the sequence of HEXA comprises instant SEQ ID NO: 1.
Stern II teaches a chimeric protein with G-CSF and HEXA that is able to cross the blood brain barrier, where the sequence of HEXA, SEQ ID NO: 26, has 99.99% sequence identity to instant SEQ ID NO: 1 ([0029]; [0019]) (see below). SEQ ID NO: 26 is an active analog of instant SEQ ID NO: 1.
It would be obvious to one of ordinary skill in the art to modify HEXA of the modified fusion protein of reference patent and Bai et al. comprising G-CSF, transferrin targeting protein, and HEXA with SEQ ID NO: 26 of Stern II, which is an active fragment of instant SEQ ID NO: 1
One of ordinary skill in the art would have been motivated to combine these teachings because Stern II teaches the same composition as the reference patent and explicitly suggests using instant SEQ ID NO: 26 in one embodiment. For this reason, there would be a reasonable expectation of success.
Claims 66-67 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. US 10265412 B2 (hereafter the reference patent) in view of Bai et al., as applied to instant claim 1, in further view of Boado et al. (Genetic engineering, expression, and activity of a fusion protein of a human neurotrophin and a molecular Trojan horse for delivery across the human blood-brain barrier, 2007, Biotechnol Bioeng, pgs. 1376-1385 (see instant PTO-892).
The modified composition of reference patent and Bai et al. teach a fusion protein comprising G-CSF, transferrin, and HEXA.
The modified composition of the reference patent and Bai et al. does not explicitly teach that the proteinaceous therapeutic agent is BDNF.
Boada et al. teaches that BDNF produces neurogenesis but can’t cross the blood brain barrier (pg. 1377, right side, first paragraph). Boado et al. teaches a fusion protein in which human BDNF is fused to the heavy chain of a chimeric antibody for the human insulin receptor (HIR) (hereafter HIRMAb-BDNF) (abstract, Fig. 2). Boado et al. teaches that HIRMAb-BDNF retained its functionality for the HIR and the receptor for BDNF. Boado et al. teaches that therapeutic levels of BDNF were produced in a primate brain after intravenous administration of the fusion protein (abstract). Boado et al. teaches that this therapy is useful for a variety of chronic and acute brain conditions such as acute ischemic stroke (pg. 1386, left side, first paragraph).
It would be obvious to one of ordinary skill in the art to substitute the HEXA of the modified fusion protein comprising G-CSF, transferrin targeting protein, and HEXA, of modified reference patent and Bai et al. with BDNF, as taught by Boada et al. to arrive at a fusion protein comprising G-CSF and transferrin targeting protein linked to BDNF via a peptide linker in order to generate a therapeutic agent to treat stroke. One of ordinary skill in the art would be motivated to substitute the therapeutic agent on the modified fusion protein in order to tailor the composition to specific treatments and maximize the applications of the composition. One of ordinary skill in the art would have a reasonable expectation of success based on the successful results of administering BDNF via fusion protein, as taught by Boado et al..
Claims 68 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. US 10265412 B2 (hereafter the reference patent) in view of Bai et al., as applied to instant claim 1, in further view of Xiong et al. (see instant PTO-892).
The modified composition of reference patent and Bai et al. teach a fusion protein comprising G-CSF, transferrin, and HEXA.
The modified composition of the reference patent and Bai et al. does not explicitly teach that the proteinaceous therapeutic agent is an antibody directed to a growth factor or growth factor receptor expressed on tumor cells in the brain.
Xiong et al. teaches that gliomas express BDNF (abstract) and that expression of mature BDNF is positively associated with glioma malignancy grade and poor prognosis in nervous system tumors (pg. 223, right side, first four lines). Xiong et al. suggests BDNF neutralizing antibodies or TrkB-receptor antibodies as a treatment for glioma (pg. 226, left side, last 5 lines).
It would be obvious to one of ordinary skill in the art to substitute HEXA of the modified fusion protein comprising G-CSF, transferrin targeting protein, and HEXA, of the reference patent and Bai et al. with a BDNF neutralizing antibody as taught by Xiong et al. to treat glioma. One of ordinary skill in the art would be motivated to substitute the therapeutic agent of the modified fusion protein in order to tailor the composition to different conditions which require delivery of molecules across the BBB in order to maximize the potential applications of the fusion protein. There would be a reasonable expectation of success substituting the therapeutic agent to a BDNF neutralizing antibody because Xiong et al. teaches that suppression of mature BDNF signaling pathway would be beneficial in treating glioma.
Claims 71 and 75 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. US 10265412 B2 (hereafter the reference patent) in view of Bai et al., in further view of US 2010/0183577 A1 (hereafter Stern II), as applied to instant claim 70 above, in further view of Shoshan-Barmatz US 20160176937 A1 (see instant PTO-892).
The modified composition of the reference patent, Bai et al. and Stern II comprises fusion protein comprising G-CSF, transferrin targeting protein, and HEXA comprising SEQ ID NO: 26 of Stern II, which is an active fragment of instant SEQ ID NO: 1
The teachings of Stern II as applied to claim 70 are described above.
Shoshan-Barmatz teaches a conjugate peptide that comprises a transferrin receptor peptide which enhances cell permeability of an N-terminal domain of the human mitochondrial protein voltage-dependent anion channel 1 (VDAC). Shoshan-Barmatz teaches that transferrin can transport large molecules and has low toxicity and high yield. Shoshan-Barmatz teaches that the transferrin domain peptide has 76.9% sequence identity to instant SEQ ID NO: 36, as addressed previously.
It would be obvious to one of ordinary skill in the art to modify the transferrin targeting protein of the modified fusion protein comprising G-CSF, transferrin targeting protein, and HEXA, wherein HEXA comprises SEQ ID NO: 26 (which is an active analog of instant SEQ ID NO: 1) of modified reference patent, Bai et al., and Stern II with SEQ ID NO: 15 of Shoshan-Barmatz et al., which is an active analog of instant SEQ ID NO: 36.One of ordinary skill in the art would have been motivated to combine these sources because Stern II teaches the same composition as the reference application and explicitly suggests SEQ ID NO: 26 which is an active fragment HEXA sequence of instant SEQ ID NO: 1 and further teaches transferrin receptor mediated transport as a method of BBB transport ([0009],[0010]). One of ordinary skill in the art would have a reasonable expectation of success using a fusion protein comprising G-CSF, HEXA, wherein HEXA comprises SEQ ID NO: 26 (which is an active fragment of instant SEQ ID NO: 1), and a transferrin targeting protein, wherein the transferrin protein comprises SEQ ID NO: 15 based on the successful results of the Tf peptide comprising SEQ ID NO: 15 in the carrier fusion protein taught by Shoshan-Barmatz et al..
Claim 72 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. US 10265412 B2 (hereafter the reference patent) in view of Bai et al., as applied to instant claim 1 above, in further view of Besman et al. US 8,129,348 B2 (see instant PTO-892).
The modified composition of reference patent and Bai et al. teach a fusion protein comprising G-CSF, transferrin, and HEXA.
The modified composition of the reference patent and Bai et al. does not explicitly teach that the sequence of G-CSF comprises instant SEQ ID NO: 11.
Besman et al. teaches SEQ ID NO: 2450, which is a biologically active protein conjugate G-CSF which has the same sequence as instant SEQ ID NO: 11, as addressed previously. Besman teaches that the conjugate has an increased plasma half-life compared to the biological version of the protein (Column 141, lines 15-20).
It would be obvious to one of ordinary skill in the art to modify the G-CSF peptide of the fusion protein comprising G-CSF, transferrin targeting protein, and HEXA of the reference patent and Bai et al. with SEQ ID NO: 2450 of Besman et al., which is identical to instant SEQ ID NO: 11.One of ordinary skill in the art would have been motivated to use the sequence taught by Besman because the phosphatase leader sequence enables secretion of G-CSF without amino-terminal modification (Besman, Column 15, lines 1-6 and 23-35). Furthermore, both sources are in the same field of endeavor, namely therapeutic protein conjugates. One of ordinary skill in the art would have a reasonable expectation of success because Besman teaches the half-life of G-CSF can be successfully increased when coupled to a peptide motif and an increased plasma half-life is desirable for therapeutic success (Column 5, lines 25-35).
Claim 74 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. US 10265412 B2 (hereafter the reference patent) in view of Bai et al., as applied to instant claim 1 above, in further view of Ceballos-Alcantarilla et al. (see instant PTO-892).
The modified composition of reference patent and Bai et al. teach a fusion protein comprising G-CSF, transferrin, and HEXA.
The modified composition of the reference patent and Bai et al. does not explicitly teach that the peptide linker comprises Gly-Gly-Ser repeats.
Ceballos-Alcantarilla et al. teaches “Repeats of glycine and serine residues represent the most commonly used type of linker to construct multidomain fusion proteins” (pg. 2, second paragraph). Ceballos-Alcantarilla et al. teaches that these linkers do not affect the main protein domains or hamper their folding (pg. 3, first paragraph). Ceballos-Alcantarilla et al. teaches a peptide with Gly-Gly-Ser repeats (pg. 10, second paragraph; Table 1).
It would be obvious to modify the peptide linker of a fusion protein comprising G-CSF, transferrin targeting protein, and HEXA, of modified reference patent and Bai et al. with a (Gly-Gly-Ser)2 linker. One of ordinary skill in the art would be motivated to do so because, as taught by Ceballos-Alcantarilla et al., the linkers are flexible and do not affect protein function. One of ordinary skill in the art would have a reasonable expectation of success because Ser/Gyl linkers are the conventional linker for fusion proteins, as taught by Ceballos-Alcantarilla et al.
Claim 76 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. US 10265412 B2 (hereafter the reference patent) in view of Bai et al., in further view of Boada et al., as applied to claim 66 above, in further view of Shoshan-Barmatz et al., as applied to claim 71 above, further in view of Besman et al., as applied to claim 72 above, and in further view of Wang et al. US 7205387 B2 (hereafter Wang) (see instant PTO-892).
The modified composition of the reference patent, Bai et al., Boada et al. teaches a fusion protein comprising G-CSF, transferrin binding protein, and BDNF.
The modified composition of the reference patent, Bai et al., and Boada et al. does not teach that the neurotrophic factor BDNF has a sequence of instant SEQ ID NO: 30. The modified composition of the reference patent and Bai et. al and Boada et al. does not teach that G-CSF has instant SEQ ID NO: 11 or that the transferrin receptor binding peptide is SEQ ID NO: 36.
Shoshan-Barmatz et al. teaches SEQ ID NO: 15 which has 76.9% sequence identity to instant SEQ ID NO: 36, which is an active fragment thereof of instant SEQ ID NO: 36.. As defined in the specification (pg. 17, lines 25-30) transferrin receptor binding peptide encompasses active fragments.
Besman et al. teaches G-CSF with a sequence of instant SEQ ID NO: 11, as discussed previously.
Wang et al. teaches SEQ ID NO: 2 is the human BDNF sequence (Column 2, lines 59-60) and is identical to instant SEQ ID NO: 30 (see below). Wang teaches an embodiment of a recombinant polypeptide that comprises a portion of SEQ ID NO: 30 to treat neurological disorders (abstract; Column 10, lines 34-45).
It would be obvious to modify BDNF, G-CSF, and the transferrin targeting protein of the modified fusion protein comprising G-CSF, transferrin targeting protein, and BDNF of reference patent al., Bai et al. and Boada et al. with the transferrin targeting protein comprising SEQ ID NO: 15 of Shoshan-Barmatz et al. (which is an active analog of instant SEQ ID NO: 36), G-CSF comprising SEQ ID NO: 2450 of Besman et al. (which is identical to SEQ ID NO: 11), and the BDNF comprising SEQ ID NO:2 (which is identical to instant SEQ ID NO: 30) of Wang et al., to arrive at the claimed invention. In other words, it would be obvious to use known sequences for transferrin, G-CSF, and BDNF for a fusion protein comprising these elements. All of these sources are in the same field of endeavor, namely therapeutic recombinant proteins. There would be a reasonable expectation of success using known peptides in the art for known components of the modified protein.
Conclusion
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/MICHELLE CALLAHAN BUCCINI/Examiner, Art Unit 1675
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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