DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim to priority from Provisional Application No. 62/811,497 filed 02/27/2019 and from PCT/US2020/020125 filed 02/27/2020 is hereby acknowledged.
Application Status
This Application is a National Entry Stage of PCT/US2020/020125 filed 02/27/2020 under 35 U.S.C. § 371.
Claim amendments filed 08/21/2025 are hereby acknowledged. Claims 2, 7, 10-13 are cancelled. Claim 1 is currently amended. Claims 26-32 are newly added. Claims 3-6, 9 and 14-25 are drawn to nonelected Species and Inventions and are still withdrawn. Claims 1, 3-6, 8-9 and 14-32 are pending. Claims 1, 8 and 26-32 are under examination in this office action.
Any objection or rejection not reiterated herein has been overcome by Applicant’s amendments and is withdrawn.
Claim Objections
Claim 32 is objected to because of the following informality: “Guassia princeps” should be written “Gaussia princeps”. There is a typographic error in “Guassia”.
Appropriate correction is required.
Claims 28-30 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Warning: Claims 3-6 are currently withdrawn. However, they are still pending and now depend upon a cancelled claim. The claims should be amended or cancelled as well.
Specification
Amendments to the Specification are hereby acknowledged.
New Rejections necessitated by Applicant’s Amendments
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 8 and 26 are rejected under 35 U.S.C. § 103 as being unpatentable over Liu ( Liu, B. et al. “The expression of functional human parathyroid hormone in a gene therapy model for osteoporosis” Cell Tissue Research, Vol. 317 (2004), pp: 57-63; previously cited), White (White, H.D. et al. “PTH circadian rhythm and PTH target-organ sensitivity is altered in patients with Adult Growth Hormone Deficiency with low BMD” Journal of Bone and Mineral Research, Vol. 22, No. 11 (2007), pp:1798-1807), Ueda (Ueda, H.R. et al. “System-level identification of transcriptional circuits underlying mammalian circadian clocks” Nature Genetics, Vol. 37, No. 2 (2005), pp: 187-192) and Nakajima (Nakajima, Y. et al. “Identification of Epha4 enhancer required for segmental expression and the regulation by Mesp2” Development, Vol. 133 (2006), pp: 2517-2525).
Regarding claims 1, 8 and 26, Liu teaches that Parathyroid Hormone (PTH) is used as a therapeutical protein, and that the naturally occurring nucleic acid sequence can be incorporated into a system for gene therapy for the treatment of osteoporosis (see title and Table 1).
Liu teaches a composition comprising a nucleic acid encoding human PTH sequence, under the control, i.e. downstream, of a synthetic CMV promoter in a vector (see “Construction of expression vectors” section, page 58, right column).
Liu teaches that gene therapy delivers protein in a more physiological and effective manner compared to drug oral administration. However, continuous expression of PTH using the constructs pCMV-PthA and pCMV-PthC in mice leads to anabolic effects of PTH on bones (see page 62, left column, second paragraph).
Liu does not teach specific response elements. Liu does not teach “a synthetic promoter comprising (1) a Core Clock response element comprising at least six E-box elements each having a sequence of CACGTG”.
White teaches that PTH circadian rhythm is altered in subjects with low Bone Mineral Density (BMD) (see title). White teaches that the circadian rhythm and pulsatile expression of PTH is disturbed, contributing to osteoporosis in these subjects, which is interpreted as these subjects with low BMD and a disturbed circadian pulsatile expression of PTH, are the ones most likely in need of PTH in gene therapy.
(see title and Abstract, “Conclusion” section”).
Ueda teaches about mammalian circadian clocks and the role of E-boxes (E/E’ boxes) in the regulation of gene expression (see title and abstract). Ueda teaches the use of E- boxes (CACGTG) and/or E’-boxes (CACGTT) (see page 187, right column, third paragraph).
Ueda teaches the analysis of gene expression controlled by enhancer elements fused to the SV40 basic (i.e. minimal) promoter (see Figure 1). Ueda teaches that the E-box from Per1 shows relatively higher activation of gene expression compared to the Per2 E’-box (see Figure 1b).
Ueda teaches that these circadian clock enhancer elements regulate gene expression in an oscillated, pulsatile -manner. Ueda teaches that these oscillations in gene expression are at the optimum, and maintained high, when Per1, Per2 and Per3 E-boxes and D-boxes are used in the recombinant, synthetic, vector (see Figures 1 and 2).
Nakajima teaches a naturally occurring enhancer sequence that is specific for vertebral skeleton and bone development, and that is comprised of six (6) E-boxes in Epha4 gene (see Figure 2). Nakajima teaches the use of a recombinant vector, fusing the 6-E boxes sequences to a reporter LacZ gene (see page 2519, Figure 2C and left column). Nakajima also teaches that this specific enhancer is regulated by bone-specific transcription factors (see page 2520, left column, “The Epha4 enhancer is activated by Mesp2 in cultured cells), which is interpreted as this configuration in enhancer sequence will likely attract binding by developmental and bone-specific transcription factors that are also circadian rhythm transcription factors, depending on base sequences in E-boxes and flanking sequences.
It would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have modified the promoter sequence of Liu, and add an enhancer sequence comprising six (6) E-boxes of Per1 as taught by Ueda and Nakajima. Liu and White provides motivation for establishing a construct for expression directed with enhancer elements capable of producing a pulsatile gene expression, restoring the circadian rhythm expression lost in subjects presenting with osteoporosis and in need of treatment. One motivated in optimizing the expression and making sure that the expression in localized in bones and spine, would have performed this modification with a reasonable and predictable expectation of success and arrived at the claimed invention.
Claim 27 is rejected under 35 U.S.C. § 103 as being unpatentable over Liu ( Liu, B. et al. “The expression of functional human parathyroid hormone in a gene therapy model for osteoporosis”. Cell Tissue Research, Vol. 317 (2004), pp: 57-63; previously cited), White (White, H.D. et al. “PTH circadian rhythm and PTH target-organ sensitivity is altered in patients with Adult Growth Hormone Deficiency with low BMD”. Journal of Bone and Mineral Research, Vol. 22, No. 11 (2007), pp:1798-1807), Ueda (Ueda, H.R. et al. “System-level identification of transcriptional circuits underlying mammalian circadian clocks”. Nature Genetics, Vol. 37, No. 2 (2005), pp: 187-192) and Nakajima (Nakajima, Y. et al. “Identification of Epha4 enhancer required for segmental expression and the regulation by Mesp2”. Development, Vol. 133 (2006), pp: 2517-2525), as applied to claim 1 above and in further view of Promega pGL4.24 (pGL4.24 certificate of analysis obtained from www.promega.com/protocols, updated November 2016) and Mizutani (Mizutani, T. et al. “C/EBPβ (CAAT/enhancer-binding protein β) mediates progesterone production through transcriptional regulation in co-operation with SF-1 (steroidogenic factor-1).” Biochemistry Journal, Vol. 460 (2014), pp: 459-471).
The rejection of claims 1, 8, and 26 is described above. The combination of references Liu, White, Ueda and Nakajima renders elements of claims 1, 8, and 26 obvious.
However, the combination of references does not teach a minimal promoter comprising 31 base pairs.
Regarding claim 27, Promega pGL4.24 teaches a plasmid that is commercially available, and that can be used for studying enhancer elements’ activities with a luciferase reporter gene (see “Description” section). Promega pGL4.24 teaches a minimal CMV promoter sequence that is 31 base pairs (see page 2).
Mizutani teaches the use of the Promega pGL4.24 (see page 461, right column, “Plasmid” section, end of first paragraph). Mizutani use the plasmid to assess gene expression regulation under a CMV minimal promoter, modified with specific genes (human CYP11A1 and human HSD3B2) enhancer elements (see page 461, “Plasmid” section). Mizutani identifies C/EBP β and SF-1 as the specific transcription factors that bind to these response elements, and was able to obtain specific transactivation using the pGL4.24 modified with these elements upstream of the CMV minimal promoter fused to reporter gene Luciferase (see Figure 3E and 5F). Mizutani teaches that this plasmid and minimal promoter is effective.
It would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have modified the vector taught by Liu modified by Ueda and Nakajima, and substituted the CMV promoter with a minimal CMV promoter as taught by Promega pGL4.24 and Mizutani. Promega pGL4.24 teaches that this construct is commercially available and Mizutani teaches that the construct with a minimal CMV promoter is functional. One with ordinary skills in the art, motivated in making sure that gene expression of a reporter gene or a therapeutic protein such as PTH is regulated by the response elements/enhancer elements exclusively without interference from ubiquitous house-keeping transcription factors, could have performed this substitution with a reasonable expectation of success as taught by Mizutani, and arrived at the claimed invention.
Claim 31 and 32 are rejected under 35 U.S.C. § 103 as being unpatentable over Liu ( Liu, B. et al. “The expression of functional human parathyroid hormone in a gene therapy model for osteoporosis”. Cell Tissue Research, Vol. 317 (2004), pp: 57-63; previously cited), White (White, H.D. et al. “PTH circadian rhythm and PTH target-organ sensitivity is altered in patients with Adult Growth Hormone Deficiency with low BMD”. Journal of Bone and Mineral Research, Vol. 22, No. 11 (2007), pp:1798-1807), Ueda (Ueda, H.R. et al. “System-level identification of transcriptional circuits underlying mammalian circadian clocks”. Nature Genetics, Vol. 37, No. 2 (2005), pp: 187-192) and Nakajima (Nakajima, Y. et al. “Identification of Epha4 enhancer required for segmental expression and the regulation by Mesp2”. Development, Vol. 133 (2006), pp: 2517-2525), as applied to claim 1 above and in further view of Stern (Stern, B. et al. “Improving mammalian cell factories: the selection of signal peptide has a major impact on recombinant protein synthesis and secretion in mammalian cells”. Trends in Cell & Molecular Biology, Vol. 21 (2007); researchgate.net).
The rejection of claim 1 is described above. The combination of references Liu, White, Ueda and Nakajima renders elements of claim 1 obvious.
However, the combination of references does not teach “a recombinant protein comprising a secretion signal”, and said secretion signal “is from Gaussia princeps or Cypridina noctiluca luciferase, erythropoietin, follicle stimulating hormone, or insulin.”
However, regarding claims 31 and 32, Stern teaches methods to improve production of recombinant proteins in mammalian cells by using a secretion signal (see title).
Stern teaches that the Gaussia luciferase signal peptide is superior to the secretion of albumin protein (see abstract). Stern teaches that albumin signal peptide is important in light of its important role in the hepatic cell where substantial amounts of albumin are synthesized and secreted into the blood circulation from the liver on a daily basis (see page 9, right column, second paragraph). Stern teaches that replacing the albumin signal peptide with a Gaussia luciferase secretion peptide resulted in more efficiency in secretion from HepG2 cells (same paragraph).
Stern also teaches that notably the recombinant humanized whole Gaussia luciferase has no toxic effect to mammalian cells (see page 9, left column, second paragraph). Stern teaches that the Gaussia luciferase signal peptide, a non-mammalian sequence, was able to operate very successfully in a cell line of human origin (see page 9, right column, second paragraph).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective date of the claimed invention to have modified the recombinant PTH taught by Liu in the vector taught by Liu modified by White, Ueda and Nakajima, with a secretion signal from Gaussia luciferase as taught by Stern. One with ordinary skills in the art, motivated in obtaining a recombinant protein that can be effectively expressed and secreted into the blood flow in large amounts and reach the organ target, could have performed this modification with a reasonable and predictable expectation of success and arrived at the claimed invention.
Response to Arguments
Applicant’s arguments, see Remarks, page 17 of 18, Section B, filed 08/21/2025, with respect to the rejections of claims 1, 2, 7 and 8 under 35 U.S.C. §102(a)(1) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, new grounds of rejections under 35 U.S.C. § 103 are made in view of Liu, White, Ueda and Nakajima.
Insofar as applicants’ arguments are applicable to the rejections set forth above in view of Liu, the arguments are not persuasive as Liu teaches gene therapy using a construct with a CMV promoter upstream of a sequence encoding PTH. The combination of Liu, White, Ueda and Nakajima renders claim 1 obvious.
One cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Allowable Subject Matter
Claims 28-30 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
Regarding claims 28-30, SEQ ID NO: 1, SEQ ID NO: 21 and SEQ ID NO: 22 appear to be free from prior art (Search results from ABSS reviewed).
Conclusion
Claims 27-30 and 32 are objected to. Claims 1, 8, 26-27 and 31-32 are rejected.
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636