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 .
Status of Claims
Claims 1-10 were originally filed on October 21st 2021.
The amendment filed on August 21st 2024, cancelled claims 2-4, and amended claims 1, 8 and 9.
The amendment filed on April 10th 2025, cancelled claims 5-6 and 10, amended claims 1 and 8 and added new claims 11-13.
The amendment filed on December 8th 2025, amended claims 1, 8, 11-12.
Claims 1 and 7-9 and 11-13 are currently pending and under consideration.
Priority
The present application claims status as a 371 (National Stage) of PCT/KR2020/005353 filed April 23rd 2020 and claims priority under 119(a)-(d) to Korean Application No. 10-2019-0049370 filed on April 26th 2019.
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d) for Korean Application No. 10-2019-0049370, which papers have been placed of record in the file. The English language translation of the certified foreign priority application was filed on 08/21/2024.
Response to Arguments
1. Applicants’ arguments, see Response, 12/08/2025, with respect to the 35 U.S.C. 112(a) first paragraph, as failing to comply with the written description requirement (i.e., new matter), have been fully considered but are not persuasive. The 35 U.S.C. 112(a) rejection to claims 11 and 12 has been maintained.
2. Applicants’ arguments, see Response, filed 12/08/2025, with respect to 35 U.S.C. 103 as being unpatentable over WO 2009/067757 A1 with International Publication Date of June 4th 2009 (herein after “757”) in view of Park et al., Process Biochemistry 49 (2014), pp. 1516-1526 (herein after “Park”), Hedegaard et al., Scientific Reports 8, article number 6327 (2018), pp. 1-14 (herein after “Hedegaard”), Hyun et al., Angew. Chem. Int. Ed. 2014, 53, pp. 10668-10672 (herein after “Hyun”), as evidenced by Nakanishi et al., Bone 51 (2012), pp. 369-375 (herein after “Nakanishi”); have been fully considered but are not persuasive. The 35 U.S.C. 103 rejection to claims 1 and 7 has been maintained.
3. Applicants’ arguments, see Response, filed 12/08/2025, with respect to 35 U.S.C. 103 as being unpatentable over WO 2009/067757 A1 with International Publication Date of June 4th 2009 (herein after “757”) in view of Park et al., Process Biochemistry 49 (2014), pp. 1516-1526 (herein after “Park”), Hyun et al., Angew. Chem. Int. Ed. 2014, 53, pp. 10668-10672 (herein after “Hyun”) and Sun et al., Bioconjugate Chem. 2016, 27, pp. 329-340 (herein after “Sun”); have been fully considered but are not persuasive. The 35 U.S.C. 103 rejection to claims 8-9 and 13 has been maintained.
Maintained/Modified Rejections in light of Amendments
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
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.
1. Claims 11 and 12 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 claims 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. This is a new matter rejection.
In the instant case, claims 11 and 12 were added (cf. amendment filed 04/10/2025) to further limit claim 1, which is directed a bone-specific complex comprising P800SO3-30Kc19-Oct4. Applicants stated in their remarks that “no new matter is introduced.” (see pg. 4 of the Remarks filed on 12/08/2025). However, the support (i.e., Example 1-3 “Preparation of complex”, Scheme 1 and pp. 6-7 of the instant specification) provided by Applicants does not support that the subject matter of claims 11 and 12 was previously presented as original claim 9 is directed to the average of bone-targeting molecules synthesized onto the recombinant protein molecule; the instant specification at lines 7-9 reads: “according to one embodiment, the complex prepared according to the above method may be optimized so that an average of 1 to 5, for example, 2 to 3, for example, 2.5 bone-targeting molecules are synthesized onto the recombinant protein molecule.” Therefore, the specification is void of support that would clearly support that the complex has an average of 1 to 5 moles of P800SO3 synthesized onto one mole of 30Kc19-Oct4. The specification does not teach that the specifically claimed bone-specific complex (i.e., P800SO3-30Kc19-Oct4) has an average of 1 to 5 moles of P800SO3; nor an average of 2 to 3 moles of P800SO3, synthesized onto one mole of the bone cell transformation recombinant protein. Accordingly, the subject matter recited in instant claims 11 and 12, has not been adequately supported.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness
(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
1. Claims 1 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2009/067757 A1 with International Publication Date of June 4th 2009 (herein after “757”) in view of Park et al., Process Biochemistry 49 (2014), pp. 1516-1526 (herein after “Park”), Hedegaard et al., Scientific Reports 8, article number 6327 (2018), pp. 1-14 (herein after “Hedegaard”), Hyun et al., Angew. Chem. Int. Ed. 2014, 53, pp. 10668-10672 (herein after “Hyun”), as evidenced by Nakanishi et al., Bone 51 (2012), pp. 369-375 (herein after “Nakanishi”)..
Regarding claim 1, a bone-specific complex comprising P800SO3-30Kc19-Oct4, wherein the bone cell complex comprises Oct4 bound 30Kc19 (30Kc19-Oct4), and P800S03 bound to 30Kc19-Oct4:
‘757 teaches a method of initiating pluripotency in a responsive mammalian cell, which comprises introducing into the cell an effective amount for inducing pluripotency within the cell of Oct4 protein or a functionally equivalent analogue, variant or fragment thereof (see ‘757, pg. 4, lines 11-14). ‘757 also teaches that the responsive mammalian cells are mammalian cells other than pluripotent stem cells, preferably one or more of hepatocytes, fibroblasts, endothelial cells, B cells, T cells, dendritic cells, keratinocytes, adipose cells, epithelial cells, epidermal cells, chondrocytes, cumulus cells, neural cells, glial cells, astrocytes, cardiac cells, esophageal cells, skeletal muscle cells, skeletal muscle satellite melanocytes, hematopoietic cells, osteocytes, macrophages, monocytes, mononuclear cells or stem cells including embryonic stem cells, embryonic germ cells, adult brain stem cells, epidermal stem cells, skin stem cells, pancreatic stem cells, kidney stem cells, liver stem cells, breast stem cells, lung stem cells, muscle stem cells, heart stem cells, eye stem cells, bone stem cells, spleen stem cells, immune system stem cells, cord blood stem cells, bone marrow stem cells and peripheral blood stem cells (see ‘757, pg. 6, lines 3-12). ‘757 also teaches that the Oct4 or analogues or variants may be produced recombinantly (see ‘757, pg. 6, lines 21-22), thereby constituting Oct4 as recited in instant claim 1. Additionally, ‘757 teaches that the Oct4 includes within the homeobox domain a sequence homologous to antennapedia/penetratin, which enables entry of the protein into the cell in the absence of additional cell-permeant peptide vectors (see ‘757, pg. 16, lines 18-20). ‘757 teaches that the term “variants” is intended to encompass the inclusion in the protein of additional functional sequences such as cell permeable peptide sequences such as the TAT sequence derived from the human immunodeficiency virus and is also intended to encompass alteration of the Penetratin-related sequence within Oct4 (DVVRVWFCNRRQKGKR) with the archetypal Penetratin sequence (RQIKIWFQNRRMKWKK) or a variant thereof (see ‘757, pg. 15, lines 18-27).
‘757 also teaches using a luciferase reporter to quantitate functionality of the recombinant protein (see ‘757, pg. 23, line 21). As evidenced by Nakanishi, luciferase targets bone (see Nakanishi, pg. 372, left column, paragraphs 1 and 2). Therefore, the teachings of ‘757 suggest the claim limitations where a bone-specific complex comprises Oct4, as recited in instant claim 1.
However, ‘757 does not expressly teach wherein the bone-specific complex comprises Oct4 bound to 30Kc19 (30Kc19-Oc4), and P800S03 bound to 30Kc19-Oc4, as recited in instant claim 1.
Park teaches that the 30Kc19 protein has cell penetrating property in various types of cells, as well as the ability to deliver cargo proteins into cells (see Park, pg. 1518, left column, paragraph 3), thereby constituting wherein the complex comprises 30Kc19 recited in instant claim 1. Park and coworkers confirmed the presence of CPP (cell penetrating peptide) in the 30Kc19 protein by expressing and purifying the truncated N- and C- terminal forms of the 30Kc19 protein (see Park, pg. 1518, left column, paragraph 3). The results indicated that N-terminal truncated domain was responsible for the cell penetrating property of 30Kc19 protein since the N-terminal segment (i.e., 30Kc191-120) was found in the cell (see Park, pg. 1518, right column, paragraph 1). Upon further investigation, Park and coworkers determined that 30Kc1945-57 which was named “Pep-c19” was found to be the cell-penetrating peptide from 30Kc19 protein that efficiently penetrated cells when supplemented into medium for mammalian cell culture (see Park, pg. 1520, left column, paragraph 1). In order to examine the ability of Pep-c19 to deliver foreign proteins into the cell as well as its cell-penetrating efficiency a GFP-Pep-c19 as well as GFP and GFP-30Kc19 were expressed and purified in E.coli (see Park, pg. 1520, left column, last paragraph). Park teaches that similar to GFP-30Kc19, GFP-Pep-c19 also penetrated into the cells (see Park, pg. 1520, right column, paragraph 1). As such, the teachings of ‘757 when combined with the teachings of Park are suggestive of a bone-specific complex comprising Oct4 bound 30Kc19, as recited in instant claim 1.
With respect to P800SO3 bound to 30Kc19-Oct4; Hyun teaches phosphonated near-infrared fluorophores for biomedical imaging of bone (see Hyun, pg. 10668, Title). Hyun’s four types of phosphonated near-infrared (NIR) fluorophores were prepared from a pentamethine core for 700nm fluorescence and a heptamethine core for 800nm fluorescence, with the addition of sulfonates as indicated (see Hyun, pg. 10668, right column, paragraph 2). Hyun also teaches that the specificity of these new NIR fluorophores for the biologically important calcium salts hydroxyapatite (HA), calcium carbonate (CC), calcium phosphate (CP), calcium oxalate (CO) and calcium pyrophosphate (CPP) was measured (see Hyun, pg. 10668, right column, paragraph 3). Hyun also reports that P800 fluorophores have a strong affinity for HA, but specificity was significantly different for molecules with additional sulfonates attached, in particular a high affinity for CP, roughly equal to that for HA, was seen with P800SO3 (see Hyun, pg. 10668, right column, paragraph 3), thereby constituting a wherein the complex comprises P800SO3 as recited in instant claim 1. Additionally, when bone targeting was explored in vivo by administering phosphonated NIR fluorophores intravenously into mice, it was found that P800SO3 was eliminated from the body by renal clearance into urine without nonspecific uptake by non-bone tissues and organs because of the low log D (distribution coefficient) values and high polarity (see Hyun, pg. 10669, right column, last paragraph). Moreover, P800S03 showed longer blood half live (t1/2β; ca. 50 min) than other NIR, thus the bone targeting and biodistribution of P800SO3 was most favorable (see Hyun, pg. 10669, right column, first paragraph). As such, the teachings of Hyun when combined with the teachings of ‘757 are suggestive of the claim limitations as recited in instant claim 1.
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of ‘757 with those of Park and Hyun and substitute the cell-penetrating peptide TAT with 30Kc19 protein taught by Park. Since the luciferase reporter of ‘757 was used to quantitate functionality of ‘757’s recombinant protein; one of ordinary skill in the art would have been motivated to incorporate the phosphonated near-infrared fluorophore P800SO3 taught by Hyun as part of ‘757’s method of inducing pluripotency within osteocytes, bone stem cells and/or bone marrow stem cells. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because a sequence homologous to antennapedia/penetratin, which enables entry of the protein into the cell in the absence of additional cell-permeant peptide vectors is naturally found within the homeobox domain of Oct4; because 30Kc19 protein was known to have cell penetrating property in various types of cells, as well as the ability to deliver foreign proteins into various cells; and because P800SO3 was known to have affinity for biologically important calcium salts such as hydroxyapatite (HA) and calcium phosphate (CP) and it was also known that P800SO3 is eliminated from the body by renal clearance into urine without nonspecific uptake by non-bone tissues and organs and has a blood half live of 50 min. Also, one of ordinary skill before the effective filing date of the claimed in invention would have had a reasonable expectation of success given that the method of ‘757 induced pluripotency in a responsive mammalian cell by introducing a recombinant protein (i.e., TAT-Oct4 protein) bound to a luciferase reporter to quantitate functionality of the recombinant protein; and given that the ability to deliver foreign proteins into cells was tested with GFP-30Kc19 by Park; and given that bone targeting was explored in vivo by administering P800SO3 intravenously to mice. Therefore, substituting TAT with 30Kc19 and the luciferase reporter with P800SO3 would support wherein the bone cell transformation recombinant protein comprises a bone cell transformation inducing factor comprising Oct4 bound to a cell permeable protein comprising 30Kc19, and wherein the bone-targeting molecule comprises P800SO3 by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention and/or the use of known technique to improve similar devices (methods, or products) in the same way and/or the application of a known technique to a known device (method, or product) ready for improvement to yield predictable results pursuant to KSR.
Regarding claim 7, wherein the complex is P800S03-30Kc19-Oct4:
‘757 teaches that the Oct4 protein is introduced into cells with the use of cell-permeant peptide vectors (see ‘757, pg. 31, claim 17), and that the cell-permeant peptide vectors include antennapedia/penetratin TAT and signal-peptide based sequences (see ‘757, pg. 32, claim 19).
Hedegaard teaches that cell-penetrating peptides have gained attention as promising drug excipients, since they can facilitate drug permeation across cell membranes constituting a major biological barrier, and fluorophores are frequently covalently conjugated to CPPs to improve detection (see Hedegaard, pg. 1, abstract). As previously discussed, P800SO3 is a near infrared fluorophore which has a strong affinity for biologically important calcium salts hydroxyapatite and calcium phosphate (see Hyun, pg. 10668 , right column, paragraph 3). Thus an ordinary skill artisan would have been motivated with reasonable expectation of success to conjugate a NIR fluorophore such as P800SO3 to the N-terminus of a cell-penetrating peptide such as 30Kc19 in order to form a bone-specific complex comprising P800S03-30Kc19-Oct4 as recited in instant claim 7.
4. Claims 8-9 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2009/067757 A1 with International Publication Date of June 4th 2009 (herein after “757”) in view of Park et al., Process Biochemistry 49 (2014), pp. 1516-1526 (herein after “Park”), Hyun et al., Angew. Chem. Int. Ed. 2014, 53, pp. 10668-10672 (herein after “Hyun”) and Sun et al., Bioconjugate Chem. 2016, 27, pp. 329-340 (herein after “Sun”).
Regarding claim 8, a method for producing a bone-specific complex comprising P800SO3-30Kc19-Oct4, the method comprising: binding a bone cell transformation inducing factor to a cell permeable protein to prepare a bone cell transformation recombinant protein; activating a bone-targeting molecule with a succinimidyl ester (NHS-ester) group to form an activated bone-targeting molecule, wherein the bone-targeting molecule comprises P800SO3; and binding the activated bone-targeting molecule to the recombinant protein, wherein the bone cell transformation inducing factor comprises Oct4 protein and the cell permeable protein comprises 30Kc19:
‘757 teaches methods of inducing pluripotency in mammalian cells which involve introducing into the cells Oct4 protein (see ‘757, pg. 1, lines 1-5), by utilizing cell-permeable peptide vectors which include TAT and other cell permeable peptides (see ‘757, pg. 6, lines 18-20). ‘757 teaches that the Oct4 or analogues or variants may be produced recombinantly (see ‘757, pg. 6, lines 21-22), and that the variants intended to encompass alteration of the Penetratin-related sequence within Oct4 (DVVRVWFCNRRQKGKR) with the archetypal Penetratin sequence (RQIKIWFQNRRMKWKK) or a variant thereof (see ‘757, pg. 15, lines 18-27), thereby constituting a method for producing a bone-specific complex, comprising binding a bone cell transformation inducing factor to a cell permeable protein to prepare a bone cell transformation recombinant protein as recited in instant claim 8. ‘757 also teaches using a luciferase reporter to quantitate functionality of the recombinant protein (see ‘757, pg. 23, line 21).
However, ‘757 does not expressly teach activating a bone-targeting molecule with a succinimidyl ester (NHS-ester) group to form an activated bone targeting molecule, wherein the bone-targeting molecule comprises P800SO3; and binding the activated bone-targeting molecule to the recombinant protein, wherein the bone cell transformation inducing factor comprises Oct4 protein and the cell permeable protein comprises 30Kc19 as recited in instant claim 8.
Park teaches that the 30Kc19 protein has cell penetrating property in various types of cells, as well as the ability to deliver cargo proteins into cells (see Park, pg. 1518, left column, paragraph 3), thereby constituting wherein the cell permeable protein comprises 30Kc19 as recited in instant claim 8.
Hyun teaches P800SO3 as a phosphonated near-infrared fluorophore for biomedical imaging of bone (see Hyun, pg. 10668, Title and pg. 10668, right column, paragraph 3). Hyun also teaches that the new molecules (i.e., P800SO3) described appear to be stably incorporated into the bone matrix without interfering with normal bone deposition (see Hyun, pg. 10670, left column, last paragraph), thereby constituting wherein the bone-targeting molecule comprises P800SO3 as recited in instant claim 8.
Sun teaches the creation of a bone mineral imaging toolkit of 21 fluorescent probes with variable spectroscopic properties, bone mineral binding affinities, antiprenylation activities, and a novel linking strategy (see Sun, pg. 329, Abstract). A series of fluorescent dyes with distinguishable emission spectra, including three popular near-infrared dyes available commercially, Alexa Fluor 647 (AF647), Sulfo-Cy5, and IRDye 800CW (800CW), were selected to generate the fluorescent BP probe “toolkit” (see Sun, pg. 332, left column, paragraph 5). Conjugation was carried out between the drug-linker intermediates (4a−4f) and the succinimidyl ester (SE) of the different fluorescent dyes under similar reaction conditions (see Sun, pg. 332, left column, paragraph 5). This new alternative route (B) to allow the facile construction of a wider fluorescent bisphosphonate “toolkit” is depicted in Scheme 1 (see Sun, pg. 332, left column, paragraph 1). The N-BPs (basic nitrogen bisphosphonates) and PCs (phosphonocarboxylates) were reacted with the appropriate epoxide via the original (A) or new (B) route, yielding the BP- or PC-linker intermediates (i.e., bone targeting molecule), respectively, which were then reacted with the activated ester of any of a diverse group of fluorescent dyes (i.e., fluorescent substance) (generally, commercially available succinimidyl esters were utilized), to afford the final fluorescent imaging probes (see Sun, pg. 332, left column, paragraph 1), thereby constituting activating a bone-targeting molecule with a succinimidyl ester (NHS-ester) group to form an activated bone-targeting molecule as recited in instant claim 8. Therefore, the teachings of ‘757 when combined with the teachings of Park, Hyun and Sun are suggestive of the claim limitations recited in instant claim 8.
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of ‘757 with those of Park, Hyun and Sun and substitute the cell-penetrating peptide TAT with 30Kc19 protein taught by Park and the luciferase reporter with the phosphonated near-infrared fluorophore P800SO3 taught by Hyun and include NHS esters (N-hydroxysuccinimide esters) and react the bisphosphonate linker intermediates with the activated ester of the fluorescent dyes as taught by Sun. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because Oct4 includes within the homeobox domain a sequence homologous to antennapedia/penetratin, which enables entry into the cell in the absence of additional cell-permeant peptide vectors; because 30Kc19 protein was known to have cell penetrating property in various types of cells, as well as the ability to deliver foreign proteins into various cells; and because P800SO3 was known as a phosphonated near-infrared fluorophore with affinity for biologically important calcium salts such as hydroxyapatite (HA) and calcium phosphate (CP); and because BPs (basic nitrogen bisphosphonates)- or PC (phosphonocarboxylates)-linker intermediates (i.e., bone targeting molecule), were known to be reacted with the activated ester of any of a diverse group of fluorescent dyes (i.e., fluorescent substance). One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because fluorescent dyes were known to be attached to bisphosphonates as well as to be activated by succinimidyl esters as taught by Sun; because 30Kc19 protein was known to have cell penetrating property in various types of cells, as well as the ability to deliver foreign proteins into various cells as taught by Park; and because P800SO3 was known to conjugate to other functional molecules and therapeutics taught by Hyun.
One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that the method of ‘757 was used to induce pluripotency in a responsive mammalian cell by introducing a recombinant protein (i.e., TAT-Oct4 protein) bound to a luciferase reporter to quantitate functionality of the recombinant protein; given that comprises introducing into a mammalian cell, a recombinant protein (i.e., TAT-Oct4) as a method of inducing pluripotency in a responsive mammalian cell; given that the 30Kc19 has the ability to deliver foreign proteins into cells as taught by Park; and given that P800SO3 is stably incorporated into the bone matrix without interfering with normal bone deposition as taught by Hyun. Therefore, reacting the primary amine chemical group at the N-terminus of 30Kc19 and reacting a NHS ester-activated P800SO3 as the bisphosphonate linker with the activated ester of a fluorescent dye would support a method for producing a bone-specific complex, comprising activating a bone-targeting molecule with a succinimidyl ester (NHS-ester) group to from an activated bone-targeting molecule, wherein the bone-targeting molecule comprises P800SO3 by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention and/or the use of known technique to improve similar devices (methods, or products) in the same way and/or the application of a known technique to a known device (method, or product) ready for improvement to yield predictable results pursuant to KSR.
Regarding claims 9 and 13, wherein an average of 1 to 5 bone-targeting molecules are synthesized onto said recombinant protein molecule, as recited in instant claim 9; and wherein an average of 2 to 3 bone-targeting molecules are synthesized onto said recombinant protein molecule, as recited in instant claim 13:
Hyun teaches that a single carboxylic acid was purposely engineered into each P800SO3 molecule, which permits conjugation to other functional molecules and therapeutics (see Hyun, pg. 10670, right column, last paragraph). For example, this chemical group could be used to attach drugs that modulate osteoblast or osteoclast or diagnostic or therapeutic radioisotopes, creating trifunctional theranostic agents (see Hyun, pg. 10670, right column, last paragraph), thereby implying that an average of 1 to 5 bone-targeting molecules are synthesized onto said recombinant protein molecule as recited in instant claim 9; and that an average of 2 to 3 bone-targeting molecules are synthesized onto said recombinant protein molecule, as recited in instant claim 13:
In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the above claims would have been obvious to one of ordinary skill in the art within the meaning of 35 U.S.C 103. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references above.
Response to Arguments
Regarding Applicants’ argument, with respect to the 35 U.S.C. 112(a) rejection to claims 11 and 12, have been considered but are not persuasive.
Applicants assert that claims 11 and 12 have adequate support in the specification as filed (see Remarks, filed 12/08/2025, pg. 5, paragraph 3). However, the instant specification filed on 10/21/2021 has been checked to the extend necessary to determine that the absence of the recitation “moles of P800SO3 synthesized onto one mole of 30Kc19-Oct4” or any recitation related to mole, mol., or an amount of substance, the International System of units relating to moles is missing. It is acknowledged that the instant specification teaches the recombinant molecule prepared with P800SO3, 30Kc19 and Oct4. The specification is silent about the amount of substance (i.e., mol.) of P800SO3 synthesized onto the amount of substance (i.e., mol.) of 30Kc19-Oct4. The specification recites the average number of P800SO3 molecules synthesized onto the amount of molecules of 30Kc19-Oct4 (see instant specification, pg. 7, lines 11-13). However, a molecule and a mol are not the same. A molecule refers to a tiny particle, while a mole is a unit for counting a huge amount of molecules, atoms, or ions (i.e., Avogadro’s number).
Accordingly, the 35 U.S.C. 112(a) rejection to claims 11 and 12 is maintained, because the specification is silent about the amount of moles of P800SO3 synthesized onto one mole of 30Kc19-Oct4.
Regarding Applicants’ arguments, with respect to the 35 U.S.C. 103 rejections to claims 1, 7-9 and 13; have been considered but are not persuasive for the following reasons:
As discussed in the action mailed on 08/12/2025, Applicants are respectfully reminded that the rejections supra are based on obviousness. Pursuant to MPEP 2142, 35 U.S.C 103 authorizes a rejection where; to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references (emphasis added). Since the rejection is based on obviousness, it is unnecessary for every claim limitation to be taught and/or suggested by a single reference.
Additionally, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In the instant case, as discussed above in the 103 rejections, the teachings of ‘757 when combined with the teachings of Park et al., Hyun et al., and Sun et al., are suggestive of the claimed limitations recited in instant claims 1, 7-9 and 13.
In other words, an ordinary skilled artisan after reading ‘757 would have been motivated with reasonable expectation of success to arrive at the claimed bone-specific complex by substituting the cell-penetrating peptide TAT with 30Kc19 as taught by Park, and the luciferase reporter with the phosphonated infrared fluorophore P800SO3 as taught by Hyun. Before the effective filing date of the claimed invention, the components to the instantly claimed bone-specific complex (i.e., Oct4, 30Kc19 and P800SO3) and their respective functions were known.
Additionally, pursuant to MPEP 2143.02(II), obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). Thus, Applicants’ assertions that ‘757, Park, Hyun and Sun provide no motivation or reasonable expectation of success in achieving a bone-specific complex as claimed are not persuasive, because there is no support in the cited prior art, nor in the instant specification, nor additional data that demonstrates that the proposed combination of references would not result in the instantly claimed bone-specific complex.
Additionally, it is the Examiner’s understanding that Applicants are arguing limitations which are not claimed. For instance, Applicants argue that Park provides no motivation for the substitution of TAT with 30Kc19 and no reasonable expectation of success since achieving a bone-specific complex since the primary and secondary structure and ability to penetrate various cells/tissues, such as the brain different from one another (see Remarks, filed 12/08/2025, pg. 8, paragraph 2).
The fact that the inventor has recognized another advantage of 30Kc19 (i.e., delivery of P800SO3 and Oct4 to bone cells/tissues) which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Even if the scope of the instant claims encompassed 30Kc19’s the primary and secondary structure and ability to penetrate various cells/tissues; and assuming arguendo that the cited art does not expressly suggest using 30Kc19 to deliver cargo into soft tissues. Since the prior art teaches that 30Kc19 is a cell-penetrating protein it would naturally follow Oct4 and P800SO3 would be delivered as cargo to bone cells via the cell-penetrating peptide 30Kc19.
As such, the reason (i.e., delivery of P800SO3 and Oct4 to bone cells/tissues) an ordinary skilled artisan would modify the teachings of ‘757 and use 30Kc19 instead of TAT as the cell-penetrating protein does not preclude a finding of obviousness. In other words, it is not necessary for the prior art to teach that 30Kc19 could be used to transduce Oct4 protein into bone cells/tissues.
With respect to Applicants’ arguments pertaining to the teachings of ‘757, wherein the “luciferase reporter” is not a bone-targeting molecule and is not bound to a bone cell transformation recombinant protein (see Remarks, filed 12/08/2025, pg. 6, second to last paragraph, and pg. 10, second to last paragraph), and that the conclusion is inconsistent with the teachings of ‘757 have been considered but are not persuasive.
As previously stated, the obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art.
As discussed in the 35 U.S.C 103 rejection above, an ordinary skill artisan would have been motivated after reading ‘757 to incorporate P800SO3 as part of a method of inducing pluripotency in cells such as osteocytes, bone stem cells and/or bone marrow stem cells with reasonable expectation of because P800SO3 was known to have a strong affinity for calcium phosphate and hydroxyapatite. And since ability of Park’s CPP to deliver foreign proteins into cells was tested with GFP-30Kc19, an ordinary skilled artisan would also have been motivated to substitute the GFP with a P800SO3 and bind 30Kc19 to P800SO3. Additionally, since it was known that succinimidyl esters were utilized to activate a diverse group of fluorescent dyes, an ordinary skilled artisan would have been motivated with reasonable expectation of success to activate the P800SO3 with an NHS-ester as taught by Sun et al. As such, the Examiner maintains that the instantly claimed invention is prima facie obvious light of the teachings of ‘757, Park et al., Hyun et al., and Sun et al.
Therefore, the Examiner maintains that the motivation to bind a near-infrared (NIR) fluorophore such as P800SO3 to the N-terminus of a cell-penetrating peptide such as 30Kc19 is to improve detection and to facilitate cargo delivery or permeation of cargo across cell membranes, and that the motivation to attach the NIR fluorophore to a CPP was known before the effective filing date of the claimed invention. Applicants’ arguments are not persuasive, because ‘757 does not necessarily have to teach or suggest the Oct4-30Kc19-P800SO3 complex of instant claim 1. Rather, the combined teachings of the cited prior art on the claimed bone-specific complex comprising a cell permeable protein (i.e., 30Kc19) and the cargo to be delivered (i.e., Oct4 and P800SO3).
Regarding Applicants’ arguments with respect to improved effect of specific delivery to bone tissue (see Remarks, filed 12/08/2025, pg. 8, paragraph 3); and remarkably low uptake in tissues other than bone (see Remarks, filed 12/08/2025, pg. 9, paragraph 2); have been considered but are not persuasive.
Although not explicitly stated, it is the Examiner’s understanding that Applicants’ arguments pertain to unexpected results. However, pursuant under MPEP 716.02(d), whether the unexpected results are the results of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” Additionally, MPEP 716.02(b) states that evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). See In re Blondel, 499 F.2d 1311, 1317, 182 USPQ 294, 298 (CCPA 1974) and In re Fouche, 439 F.2d 1237, 1241-42, 169 USPQ 429, 433 (CCPA 1971) for examples of cases where indirect comparative testing was found sufficient to rebut a prima facie case of obviousness.
With respect to the scope of the claimed bone-specific complex as recited in instant claim 1, and the unexpected results of improved effect of specific delivery to bone tissue achieved by the claimed bone-specific complex and the remarkable effects that are not rendered obvious to one of ordinary skill in the art by the cited references. The Examiner acknowledges the increase in gene expression level when Oct4-30Kc19 was used to induce vascular endothelial cells to osteoblast and when P800SO3-30Kc19 was used to induce specific delivery to bone. However, unexpected results of superior delivery uptake and/or low uptake by other tissues may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art. In the instant case, ‘757 teaches Fig. 4, which shows the amino acid sequence of Oct4-TAT construct (see pg. 7, line 24, and Fig. 4); and Fig. 2 which shows a bar graph of luciferase measurements (relative luciferase units) in two cell lines stably transfected with Oct4-TAT construct (see pg. 7, lines 11-12, and Fig. 2). Thus, the “unexpected” results of improved specific delivery to bone tissue, the markedly low uptake in tissues other than bone, need to be demonstrated relative to the closest prior art.
Also, with respect to the delivery of proteins to specific bone structures by the P800SP3-30Kc19 complex is a novel finding that has not been previously disclosed (see Remarks, filed 12/08/2025, pg. 9, paragraph 1). Pursuant to MPEP 1504.03, a claimed design that meets the test of novelty must additionally be evaluated for nonobviousness under 35 U.S.C 103.
The instantly claimed bone-specific complex might be novel, however, the structure and function of the individual parts (i.e., Oct4, P800SO3 and 30Kc19) was known before the effective filing date of the claimed invention. Thus on ordinary skilled artisan would have been motivated with reasonable expectation of success to combine the teachings of the individual references (i.e., ‘757, Park, Hedegaard, Hyun and Sun) in order to arrive at the claimed invention.
Accordingly, the U.S.C 103 rejections to claims 1, 7-9 and 13 are maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
/CLAUDIA ESPINOSA/Patent Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654