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 .
Claim Status
Claims 28-36 are pending.
Claims 32 and 36 are currently amended.
Claims 1-27 are cancelled.
Claims 28-36 have been examined.
Priority
This application is a 371 of PCT/KR2020/006491 05/18/2020
KOREA, REPUBLIC OF 10-2019-0058369 05/17/2019
New Ground of Rejection
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 36 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 36 is drawn to co-administration of the cyclo(his-pro) and PTH with all possible means known in the art comprising simultaneously, separately, or sequentially, but fails to further limit the co-administration of the cyclo(his-pro) and PTH in claim 32.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Modified Rejection
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.
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.
1. Claims 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over Lindsay et al. (Osteoporos Int (2016) 27:2395–2410, previously cited 10/1/2025) in view of Fraher et al. (J Clin Endocrinol Metab. 1992 Aug;75(2):417-23, previously cited 4/22/2025), Jimi et al. (Nat Med. 2004 Jun;10(6):617-24, previously cited 4/22/2025) and Minelli et al. (Int J Biochem Cell Biol. 2012 Mar;44(3):525-35, previously cited 4/22/2025).
Claim 28 is drawn to a method of treating a bone loss-related disease comprising:
administering an effective amount of a composition consisting of
(i) a cyclo(his-pro) (CHP) or a pharmaceutically acceptable salt thereof;
a pharmaceutically acceptable carrier; and
a parathyroid hormone (PTH)
wherein the administration of the composition increases osteoblast differentiation and/or bone formation compared to an administration of PTH alone. The wherein clause claims the treatment effect of administering the combination without changing the active ingredients of a parathyroid hormone or a cyclo(his-pro); thus a combination of prior art references teaching a method of administering a parathyroid hormone and a cyclo(his-pro) to treat a bone loss-related disease meets the claim limitations.
Lindsay et al. teach Teriparatide (TPTD) is the only currently available therapeutic agent that increases the formation of new bone tissue and can provide some remediation of the architectural defects in the osteoporotic skeleton, reading on treating a bone loss-related disease. Lindsay et al. teach Teriparatide (TPTD) is a recombinant human parathyroid hormone PTH 1-34 (p2395, col 2, Introduction), reading on the limitation (iii). Although Lindsay et al. teach administration of Teriparatide via injection without specifying a pharmaceutically acceptable carrier, Fraher et al. is cited to show the use of 0.9% saline as a pharmaceutically acceptable carrier known in the art, reading on the limitation (ii).
Lindsay et al. in view of Fraher et al. do not teach further administration of a cyclo(his-pro) to treat a bone loss-related disease.
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Jimi et al. teach bone resorption is a major pathological factor in chronic inflammatory diseases such as periodontitis, osteoporosis and arthritis, and it is now clear that deregulation of immune and inflammatory responses is crucial in initiating the bone destruction associated with these conditions known in the art (p617, col 1, para 1, 1st sentence). Jimi et al. teach selective inhibition of NF-κB activation offers an effective therapeutic approach for inhibiting chronic inflammatory diseases involving bone resorption (Title and Abstract), which teaches inhibition of NF-κB activation to treat bone loss-related diseases including osteoporosis and motivates one of ordinary skill in the art to beneficially combine PTH (1-34) and an NF-κB inhibitor for the same purpose to treat osteoporosis. Minelli et al. teach that cyclo(His-Pro) suppresses the proinflammatory NF-κB signaling via the Nrf2-mediated heme oxygenase-1 activation (Abstract) demonstrated by the data shown above (p533, Fig. 6A). Because Minelli et al. show cyclo(His-Pro) alone is effective to inhibit NF-κB signalling (b) Jimi et al. teach selective inhibition of NF-κB activation offers an effective therapeutic approach for inhibiting chronic inflammatory diseases comprising osteoporosis, and (c) Lindsay et al. in view of Fraher et al. teach administration of PTH (1-34) in 0.9% saline for the same purpose of treating osteoporosis, one of ordinary skill in the art would have found it obvious to combine Lindsay’s PTH (1-34) and Minelli’s cyclo(His-Pro) in Fraher’s 0.9% saline for co-administration to treat osteoporosis, reading on the limitations (i)-(iii) in claim 28.
One of ordinary skill in the art before the effectively fining date of this invention would have found it obvious to combine Lindsay et al. with Fraher et al. because (a) Lindsay et al. teaches administration of PTH (1-34), a recombinant human parathyroid hormone, to treat patient’s osteoporosis and (b) Fraher et al. is cited to show the use of 0.9% saline as a pharmaceutically acceptable carrier for administration of PTH 1-34 (p418, col 1, para 1) to treat human diseases. The combination would have reasonable expectation of success because both references teach PTH 1-34.
One of ordinary skill in the art before the effectively fining date of this invention would have found it obvious to combine (i) Lindsay et al. in view of Fraher et al. with (ii) Jimi et al. and (iii) Minelli et al. because (a) Lindsay et al. in view of Fraher et al. teach administration of PTH (1-34) in 0.9% saline to treat osteoporosis, (b) Jimi et al. teach inhibition of NF-κB activation for inhibiting chronic inflammatory diseases, e.g., osteoporosis (Title and Abstract; p617, col 1, line 1-2), and (c) Minelli et al. show cyclo(His-Pro) alone is effective to inhibit NF-κB signalling (p533, Fig. 6A). The combination would have reasonable expectation of success because Minelli et al. show cyclo(His-Pro) alone is effective to inhibit NF-κB signalling and Jimi et al. teach inhibition of NF-κB activation for inhibiting chronic inflammatory bone resorption, e.g., osteoporosis.
With respect to claim 29, Lindsay et al. teach Teriparatide (TPTD) is a recombinant human parathyroid hormone PTH 1-34 (p2395, col 2, Introduction).
With respect to claim 30, Lindsay et al. (Abstract) and Jimi et al. (Title and Abstract) teach treatment of a bone loss-related disease as osteoporosis.
Applicant’s Arguments
The cited references do not teach or suggest the claimed combination set forth in claims 28-36 because there is no basis to reasonably expect that CHP would promote osteoblast differentiation or osteogenic marker expression, nor that co-administration of CHP with PTH would enhance osteoanabolic outcomes relative to PTH alone. The enhancement of osteoblast differentiation and bone formation attained by the claimed method therefore could not have been predicted from the asserted references, individually or in combinations (Remarks, p6 to p7, para 1).
Lack of Motivation and Reasonable Expectation of Success (Remarks, p7, para 2)
Teaching Away from Combining alendronate (a non-peptide compound) with PTH, Exhibits A-C, (Remarks, p7, last para to p9, para 1-2).
Response to Arguments
Applicant's arguments filed 12/31/2025 have been fully considered but they are not persuasive for the reasons as follows.
Applicant’s arguments A and B are not persuasive for the reasons as follows.
Lindsay et al. in view of Fraher et al., Jimi et al. and Minelli et al. teach beneficial combination of PTH (1-34) and cyclo(his-pro) (CHP) in a composition (simultaneous administration) or in separate compositions (sequential or separate administration) to treat osteoporosis (a bone loss-related disease in claim 30) in a patient. MPEP 2112.01 (II) states "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In the present case, the prior art composition comprising PTH (1-34) and cyclo(his-pro) is identical to the claimed composition capable of treating the same osteoporosis in claims 28-30; thus, the prior art composition must have the inseparable properties of increases osteoblast differentiation and/or bone formation compared to an administration of PTH alone as claimed.
Prima Facie Obviousness Is Not Rebutted by Merely Recognizing Additional Advantages or Latent Properties Present But Not Recognized in the Prior Art. See MPEP 2145.
Rationale different from applicant’s reason to combine prior art references is permissible. See MPEP 2144. In the present case, the rationale to beneficially combine PTH (1-34) and cyclo(his-pro) in a method to treat a subject with osteoporosis taught by cited references described above not repeated. The wherein clause does not further add a manipulated step to the method; thus the same composition comprising PTH (1-34) and cyclo(his-pro) administered to a patient to treat the same osteoporosis would be necessary to achieve the same therapeutic effect as argued by applicant.
Applicant’s argument C is not persuasive because (i) the argument is not commensurate in the scope of the rejected claims requiring co-administration of PTH and a dipeptide of cyclo(his-pro), (ii) applicant failed to provide a direct data comparison with co-administration of PTH (1-34) and a dipeptide of cyclo(his-pro) as taught by the cited references described above, and (iii) none of the cited prior art references of record teach or suggest that PTH (1-34) and a dipeptide of cyclo(his-pro) CANNOT be combined for co-administration to treat osteoporosis in a subject.
2. Claims 28-30, 32-34, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Lindsay et al. in view of Fraher et al., Jimi et al. and Minelli et al. as applied to claims and further in view of Alles et al. (Endocrinology 151: 4626–4634, 2010).
Claim 32 is drawn to a method of improving a therapeutic effect of parathyroid hormone (PTH) on a bone loss-related disease comprising (i) co-administration of PTH and cyclo(his-pro) to a subject and (ii) the co-administration increases osteoblast differentiation and/or bone formation as measured by an increase in alkaline phosphatase (ALP) activity, compared to administration of the second composition alone.
Lindsay et al. in view of Fraher et al., Jimi et al. and Minelli et al. teach co-administration of PTH and an NF-κB suppressor of cyclo(his-pro) to a subject with osteoporosis, satisfy the limitation (i) described in the rejection above.
Lindsay et al. in view of Fraher et al., Jimi et al. and Minelli et al. do not specify the co-administration increases osteoblast differentiation and/or bone formation.
Similarly, Alles et al. teach bone degenerative diseases, including osteoporosis, impair the fine balance between osteoclast bone resorption and osteoblast bone formation. Alles et al. demonstrated that inhibition of NF-κB increases osteoblast differentiation and bone formation in vitro by up-regulating the mRNAs of osteoblast-specific genes like type I collagen, alkaline phosphatase, and osteopontin. In addition, an established NF-κB inhibitor of S1627 was able to increase bone formation and repair bone defect in a murine calvarial defect model (Abstract). Alles et al. show inhibition of NF-κB can be measured by an increase in alkaline phosphatase as follows (p4628, Fig. 1A and 1C), reading on the limitation (ii) in claim 32.
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With respect to claim 33, Lindsay et al. teach Teriparatide (TPTD) is a recombinant human parathyroid hormone PTH 1-34 (p2395, col 2, Introduction).
With respect to claim 34, Lindsay et al. (Abstract) and Jimi et al. (Title and Abstract) teach treatment of a bone loss-related disease as osteoporosis.
With respect to claim 36, Lindsay et al. in view of Fraher et al., Jimi et al. and Minelli et al. teach co-administration of PTH and an NF-κB suppressor of cyclo(his-pro) to a subject with osteoporosis. One of ordinary skill in the art would found it obvious for simultaneous co-administration when PTH and cyclo(his-pro) can be formulated together for the same route of administration. Alternatively, PTH and cyclo(his-pro) can be formulated separately for co-administration separately or sequentially.
Response to Arguments
Applicant's arguments filed 12/31/2025 have been fully considered but they are not persuasive. See response to arguments above. In particular, Alles et al. is cited to show inhibition of NF-κB increases osteoblast differentiation and bone formation in vitro by up-regulating the mRNAs of osteoblast-specific genes like type I collagen, alkaline phosphatase, and osteopontin. In addition, an established NF-κB inhibitor of S1627 was able to increase bone formation and repair bone defect in a murine calvarial defect model (Abstract).
3. Claims 28-36 are rejected under 35 U.S.C. 103 as being unpatentable over Lindsay et al. in view of Fraher et al., Jimi et al., Minelli et al. Alles et al. and further in view of Kawaguchi (Clin Case Rep Rev. 2015; 1(9): 194-198, previously cited 4/22/2025).
Claim 31 and 35 are directed to osteoporosis is caused by a decrease in female hormone levels, or the destruction or inhibition of the activity of osteoblasts.
Lindsay et al. in view of Fraher et al., Jimi et al., Minelli et al., and Alles et al. teach a method of treating a patient with osteoporosis comprising administering a composition consisting of (i) cyclo(His-Pro) (CHP) or a pharmaceutically acceptable salt thereof, (ii) a pharmaceutically acceptable carrier of 0.9% saline, and (iii) a parathyroid hormone (PTH 1-34).
Lindsay et al. in view of Fraher et al., Jimi et al., Minelli et al., and Alles et al. do not specify a cause of a treated osteoporosis.
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Kawaguchi teaches age-related bone loss can be classified into two categories: systemic abnormality and osteoblast dysfunction (Abstract). Kawaguchi suggests decrease of female hormone of estrogen in systemic abnormality or destruction/inhibition (reading dysfunction) of the activity of osteoblast via intrinsic or local factors resulting in osteoporosis shown as follows (p1, Fig 2), reading on claims 31 and 35.
One of ordinary skill in the art before the effective date of this invention would have found it obvious to combine (i) Lindsay et al. in view of Fraher et al., Jimi et al., Minelli et al., and Alles et al. with (ii) Kawaguchi’s teaching of osteoporosis because (a) Lindsay et al. in view of Fraher et al., Jimi et al., Minelli et al., and Alles et al. teach a method of treating osteoporosis and (b) Kawaguchi suggests decrease of female hormone of estrogen in systemic abnormality or destruction/inhibition (reading dysfunction) of the activity of osteoblast via intrinsic or local factors resulting in osteoporosis (p1, Fig 2). The combination would have reasonable expectation of success because both Lindsay et al. and Kawaguchi osteoporosis.
Response to Arguments
Applicant's arguments filed 12/31/2025 have been fully considered but they are not persuasive. See response to arguments above.
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 28-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8 and 12-13 of copending Application No. 18/476,630 (the ‘630 application dated 9/28/2023) in view of Lindsay et al. (previously cited 4/22/2025), Fraher et al. (previously cited 4/22/2025), Jimi et al. (previously cited 4/22/2025), and Minelli et al. (previously cited 4/22/2025).
Claims 8 and 12-13 of the ‘630 application disclosed a compound of cyclo(His-Pro).
Claims 8 and 12-13 of the ‘630 application do not specify a combination of cyclo(His-Pro) and a parathyroid hormone to treat a bone loss-related disease.
The relevancy of Lindsay et al. in view of Fraher et al., Jimi et al., and Minelli et al., as applied to claims 28-30 described above not repeated here.
Because Lindsay et al. in view of Fraher et al., Jimi et al., and Minelli et al. teach beneficial combination of PTH (1-34) and cyclo(His-Pro) to treat osteoporosis, one of ordinary skill in the art would have found it obvious to combine claims 8 and 12-13 of the ‘630 application with Lindsay in view of Fraher et al., Jimi et al. and Minelli et al.
Thus, claims 8 and 12-13 of the ‘630 application in view of Lindsay et al., Fraher et al., Jimi et al. and Minelli et al. are obvious to the instant claims 28-30.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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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/J.L/Examiner, Art Unit 1658
01-March-2026
/LI N KOMATSU/ Primary Examiner, Art Unit 1658