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 .
Summary
Receipt of Applicants Arguments, Remarks and Amendments filed on 06/24/2026 is acknowledged. Claims 1-15 are pending. Claims 1-2 are amended. Claims 4-6 are cancelled. Claims 16-22 are new. Applicant elected Group I without traverse, claims 1-8, drawn to a calcified tissue substitute, was made FINAL in the prior Office Action of 03/24/2026, and remains of record. New claims 16-22 are directed to the elected invention of Group I and are examined herewith. Group II, claims 9-15 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1-3, 7-8, 16-22 are pending and under examination in this application.
Priority
The current application filed on January 05, 2024 is a continuation-in-part of U.S. Application No. 18/454, 753, filed August 23, 2023, which is a continuation of U.S. Application No. 16/618,684, filed December 2, 2019, which is a U.S. National Stage under 35 U.S.C. § 371 of international Application No. PCT/AU2018/050541, filed June 01, 2018, which claims the priority benefit of Australian Application No. AU 2017902108, filed June 02, 2017.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/05/2024 are in compliance with the provisions of 37 CFR 1.98. Accordingly, the information disclosure statements has been considered by the examiner. Signed copies have been attached to this office action.
Claim Rejections - 35 USC § 112 – Withdrawn
The rejections of claims 1 and 2 under 35 U.S.C. § 112(b) set forth in the prior Office Action are withdrawn in view of Applicant's amendment. Claim 1 has been amended to replace "mm" with "µm" throughout, consistent with the specification (¶¶ 0052-0057, 0104, 0107). Claim 2 has been amended to specify a "weight-to-weight" ratio, which finds support at ¶ 0120 of the specification. These particular indefiniteness issues are resolved. However, the amendment incorporating former dependent claims 4-6 into claim 1 introduces new indefiniteness issues, set forth below, that were not present in and could not have been raised against any previously pending claim.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
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.
Claims 1-3, 7-8 and 16-22 are 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.
(1) Lack of clear antecedent relationship between the "first portion" and "second portion" of ground nacre, and unclear scope of the particle-size limitation as to the second portion.
Claim 1, step (i), recites reacting "a first portion of ground nacre... wherein said ground nacre has a particle size of 200 µm or less" with monocalcium phosphate and water. Step (iii) subsequently recites reacting "a second portion of ground nacre" with the ground brushite from step (ii). The claim does not establish that the "first portion" and "second portion" of ground nacre are two portions of a single, common quantity of starting material introduced earlier in the claim; "a second portion of ground nacre" is introduced without clear antecedent basis tying it back to the "ground nacre" of step (i). Consequently, it cannot be determined with reasonable certainty whether: (a) the second portion is drawn from the same batch of ground nacre as the first portion and is therefore subject to the same 200 µm or less particle-size limitation; or (b) the second portion is a separately introduced quantity of ground nacre not subject to any particle-size limitation at all. Because particle size is expressly disclosed in the specification as affecting the setting behavior and reactivity of the composition, this ambiguity is not merely semantic but affects the metes and bounds of the claim. Appropriate clarification is required, for example by amending step (iii) to recite "a second portion of said ground nacre" or otherwise expressly tying the second portion to the particle-size-limited nacre of step (i).
(2) Ambiguous conjunction in step (iii) as to whether carbonate apatite is a component of "said substitute composition" or a separate co-product.
Claim 1, step (iii), recites reacting the second portion of ground nacre with the ground brushite, tetracalcium phosphate, and the recited agent "in a solution comprising disodium hydrogen phosphate... to form said substitute composition, and carbonate apatite." This phrasing is amenable to at least two inconsistent readings: (a) the reaction forms "said substitute composition," which includes carbonate apatite among its components; or (b) the reaction forms two distinct products — "said substitute composition" on the one hand, and "carbonate apatite" as a separate, non-limiting co-product on the other, not itself part of the substitute composition. This ambiguity is material because claim 1 goes on to recite that "said substitute composition" has "a final setting time (Tf) of between 60 min to 120 min," and dependent claims 16-19 and 22 each further characterize properties of "the substitute composition of claim 1." A POSA cannot determine with reasonable certainty whether the recited Tf and other downstream properties are properties of a composition that includes the carbonate apatite reaction product, or of a composition from which the carbonate apatite has been excluded or separated. Appropriate clarification is required, for example by amending the claim to recite that carbonate apatite is formed "as part of" or "as a component of" said substitute composition, if that is Applicant's intended meaning.
3. Claim 1 recites EP1-A in step (iii). The specification do not define the acronym EP1-A or what it does. Thus it is considered indefinite because neither a POASA nor the Examiner can determine the metes and bounds of “an agent selected from the group consisting of …EP1A” without knowing what the term denotes.
Claims 2-3, 7-8, and 16-22 are rejected under § 112(b) as depending from, and thus incorporating, the indefinite subject matter of claim 1.
New Rejections Necessitated by 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.
Claim(s) 1-3, 7-8, and 16-22 are rejected under 35 U.S.C. 103 as being unpatentable over Ni (Nacre surface transformation to hydroxyapatite in a phosphate buffer solution, Biomaterials 24:4323-4331 (2003); “Ni”) in view of Simon (US 2006/0233849 A1; “Simon”), further in view of Khairoun (US 2010/0068243 A1; “Khairoun ’243”), further in view of Khairoun 1997a (Khairoun et al., Effect of calcium carbonate on the compliance of an apatitic calcium phosphate bone cement, Biomaterials 18(23):1535-1539 (1997); “Khairoun ’97a”), further in view of Khairoun 1997b (Khairoun et al., Effect of calcium carbonate on clinical compliance of apatitic calcium phosphate bone cement, J. Biomed. Mater. Res. (Appl. Biomater.) 38(4):356-360 (1997); “Khairoun ’97b”), further in view of Chen (Chen et al., Phase transformation on bone cement: Monocalcium phosphate monohydrate into calcium-deficient hydroxyapatite during setting, Ceramics International 39(3):2451-2455 (2013); “Chen”), further in view of Shimada (Shimada et al., Properties of Injectable Apatite-Forming Premixed Cements, J. Res. Natl. Inst. Stand. Technol. 115(4):233-241 (2010); “Shimada”), and further in view of Lee (US 6,331,312 B1; “Lee”).
Claim 1 as amended incorporates the subject matter of former dependent claims 4-6 into a single, integrated combination and adds new limitations not previously presented in any claim, including the requirement that ground nacre have a particle size of 200 µm or less, that the ground brushite have a particle size of 30 µm or less, that tetracalcium phosphate have a particle size of 2 µm to 20 µm, that the substitute composition further include carbonate apatite as a reaction product, and that the substitute composition have a final setting time (Tf) of between 60 min to 120 min. None of these limitations, individually or in the specific combination now claimed, was previously presented for examination. The new grounds of rejection set forth below, including the newly cited references, are necessitated by this amendment.
The amendment to claim 1 necessitates the addition of Khairoun ’97a, Khairoun ’97b, Chen, Shimada, and Lee to the previously applied combination of Ni, Simon, and Khairoun ’243, because claim 1 as amended now recites, in a single integrated combination, particle-size limitations for nacre, brushite, and tetracalcium phosphate, a required bioactive/therapeutic agent, a carbonate apatite reaction product, and a final setting time of 60-120 minutes. Each new reference is directed to filling a specific, identified gap in the combination as it existed prior to amendment, as set forth below.
A. Summary of base combination (carried forward from the prior Office Action):
Ni discloses that nacre (mother-of-pearl), an organic/inorganic biocomposite of aragonite mineral comprising calcium carbonate (CaCO₃) and bioactive proteins, transforms to hydroxyapatite (HAP) when soaked in a phosphate buffer solution at room temperature via a dissolution-precipitation mechanism in which calcium ions released from the nacre aragonite surface react with phosphate ions in solution (Abstract; pp. 4324-4328). Ni establishes that nacre is a reactive CaCO₃-bearing biomineral in aqueous phosphate media and discloses nacre's osteoinductive and bone-bonding properties, its use in dental and orthopedic bone repair, and its favorable mechanical properties relative to other bone substitute materials (Introduction; p. 4329).
Simon discloses a composite bone graft material comprising a calcium matrix component and porogen particles (Abstract), including monocalcium phosphate monohydrate (MCPM, ¶ 0026), dicalcium phosphate dihydrate (DCPD/brushite, ¶ 0027), and tetracalcium phosphate (TTCP, ¶ 0028) as calcium matrix components, and bone morphogenetic proteins, antibiotics, anti-inflammatory agents, and growth factors as bioactive agents (¶ 0043, ¶ 0070, claim 16). Simon further discloses that demineralized mollusk nacre is a preferred osteoinductive DBM substitute porogen (¶ 0063, claim 6), and that combining a nacre-derived porogen with a calcium phosphate matrix of differential resorption rate is a design principle for enhancing in vivo pore formation and osteoblast colonization (¶ 0021).
Khairoun ’243 discloses a macroporous, highly resorbable apatitic calcium phosphate cement (CPC) comprising an inorganic component of calcium phosphate compounds including MCPM, DCPD/brushite, and TTCP (¶ 0049, ¶ 0052), set with a Na₂HPO₄ liquid phase, preferably 2-3% by weight (¶ 0062, ¶ 0091, ¶ 0104). Khairoun ’243 discloses that CPC setting time depends on the particle sizes of the powder components (¶ 0065), that particle size control by grinding and sieving is routine (¶ 0098), and discloses calcium carbonate as a CPC-relevant compound (¶ 0068) as well as working CPC formulations containing CaCO₃ alongside CaHPO₄ and α-TCP with confirmed in vivo bone formation in a rabbit femur model (¶¶ 0083-0084, 0129-0139).
B. New reference: Khairoun ’97a and Khairoun ’97b — CaCO₃ as a functional, non-retarding component of Na₂HPO₄-accelerated apatitic cements:
Applicant argues that Khairoun ’243 ¶ 0068 discloses calcium carbonate solely as a setting retarder, and that a POSA would therefore have been taught away from using a CaCO₃-bearing material such as nacre as a reactive component of the claimed cement. This argument does not account for the broader body of work by the same research group (I. Khairoun, M.G. Boltong, F.C.M. Driessens, J.A. Planell) directed specifically to the functional role of calcium carbonate in Na₂HPO₄-accelerated apatitic calcium phosphate cements.
Khairoun ’97a discloses three apatitic cement formulations: Biocement H (α-tricalcium phosphate and precipitated hydroxyapatite, no CaCO₃), Biocement B2 (Biocement H plus added CaCO₃), and Biocement B1 (Biocement H plus added CaCO₃ with simultaneous adjustment of the precipitated hydroxyapatite content), with the liquid/powder ratio and the percentage of Na₂HPO₄ accelerator in the cement liquid varied as the controlled process parameters. Khairoun ’97a reports that "[f]or Biocement H there was no combination of L/P ratio and percentage Na₂HPO₄ for which all clinical requirements were satisfied. However, there was an area of full compliance for Biocements B1 and B2, of which that for B1 was the largest." (abstract). Khairoun ’97b independently confirms the same finding in a companion formulation set (Biocement D, containing CaCO₃, versus Biocement F, without CaCO₃), reporting that "Biocement D showed a much larger area of full compliance and it covered both doughlike and injectable pastes," whereas the CaCO₃-free formulation had only "a small area" of compliant dough-like formulations (abstract).
Khairoun ’97a and ’97b thus establish, from the same research group responsible for Khairoun ’243, that incorporation of CaCO₃ into a Na₂HPO₄-accelerated apatitic calcium phosphate cement functionally expands the combination of liquid/powder ratio and Na₂HPO₄ concentration over which the cement satisfies clinical setting-time requirements, including enabling injectable (i.e., longer-working-time) formulations not achievable without CaCO₃. A POSA of ordinary skill, aware of Khairoun ’243's disclosure that CaCO₃ can modify CPC setting behavior and aware of the same inventors' own published data in Khairoun ’97a/’97b demonstrating that CaCO₃ addition widens the compliant, longer-setting-time processing window of a Na₂HPO₄-accelerated cement, would not have understood Khairoun ’243 ¶ 0068 as teaching away from using a CaCO₃-bearing reactant such as nacre. To the contrary, the cited art as a whole — including the inventor's own prior publications — affirmatively motivates the use of a CaCO₃ source, such as nacre, in a Na₂HPO₄-set apatitic cement system as a means of achieving a longer, clinically suitable setting time.
C. New reference: Chen — reactive CaCO₃ + MCPM → brushite chemistry, addressing the demineralized-nacre argument
Applicant argues that Simon's disclosed demineralized mollusk nacre (¶ 0063-0064) cannot perform the reactive CaCO₃ chemistry required by claim 1 step (i), because demineralization removes the aragonite/CaCO₃ mineral phase. Chen resolves this argument directly and independently of Simon. Chen discloses a calcium phosphate cement prepared from a mixture of monocalcium phosphate monohydrate (MCPM) and CaCO₃ as the solid phase, combined with a sodium phosphate buffer (SPB) solution as the liquid phase, and confirms by X-ray diffraction and electron microscopy that "MCPM and CaCO₃ reacted with sodium phosphate immediately to form dicalcium phosphate dihydrate (DCPD)" — i.e., brushite — which subsequently converts to an intermediate amorphous calcium phosphate and then to calcium-deficient hydroxyapatite.
Chen thus independently confirms, in a system entirely unrelated to Simon or to nacre specifically, that undemineralized, particulate CaCO₃ reacts directly with MCPM in an aqueous phosphate-containing liquid to form brushite — precisely the reaction recited in claim 1 step (i). Because ground nacre is, as Ni establishes, a natural, undemineralized CaCO₃/aragonite-bearing material, Chen's teaching that particulate CaCO₃ (of any origin) undergoes this reaction with MCPM confirms that a POSA would have had a reasonable expectation that undemineralized ground nacre — rather than Simon's demineralized nacre porogen — would perform the same chemistry. The combination therefore no longer relies on Simon's demineralized nacre for the reactive chemistry of step (i); Simon is relied upon only for its teaching that a nacre-derived material combined with brushite/DCPD in a bone substitute composite was a known, desirable target composition (¶ 0021, ¶ 0063), while Ni and Chen together supply the motivation and reasonable expectation of success that undemineralized nacre, as a CaCO₃ source, will react with MCPM to form brushite.
D. New reference: Lee (US 6,331,312 B1) — carbonate apatite as a known reaction product of CaCO₃-containing calcium phosphate systems
Claim 1 as amended requires that the substitute composition further comprise carbonate apatite as a reaction product of step (iii). Lee, in its background discussion (column 1, line 22 to column 4, line 29) of calcium phosphate cement chemistry, identifies as known in the art "the formation of a carbonated apatite from the reaction of monocalcium phosphate monohydrate, beta-tricalcium phosphate, alpha-tricalcium phosphate, and calcium carbonate in a sodium phosphate solution." This confirms that the formation of carbonate apatite from the reaction of a CaCO₃-bearing component with one or more calcium phosphate compounds in a sodium phosphate liquid was well known in the art as of Lee's filing date, well before the effective filing date of the claimed invention. Given that claim 1 step (iii) combines ground nacre (a CaCO₃ source, per Ni), ground brushite, and TTCP in a Na₂HPO₄ solution — materially the same class of reactants identified in Lee as forming carbonate apatite — the formation of carbonate apatite as a reaction product is the predictable result of combining known reactants under known conditions, not an unexpected or patentably distinct outcome.
E. New reference: Shimada — TTCP particle size and phosphate-salt concentration as result-effective variables controlling setting time up to and beyond 60 minutes
Applicant argues that Khairoun ’243's disclosed setting times (¶ 0065, "about 10 to about 60 min, preferably about 10 to about 30 min") do not overlap with the claimed final setting time (Tf) of 60-120 minutes. Shimada resolves this gap. Shimada discloses premixed apatite-forming calcium phosphate cements in which both the concentration of a soluble phosphate salt (NaH₂PO₄) and the particle size distribution of tetracalcium phosphate (TTCP) were varied, and reports that these two variables had a statistically significant (p < 0.01) effect on setting time, with measured setting times "found to range from (4.3 ± 0.6 to 68 ± 3) min." (abstract). Shimada further notes that "[p]revious studies reported premixed calcium phosphate cements... [with] setting times of greater than 60 min," confirming that CPC setting times extending beyond 60 minutes, and controllable via TTCP particle size and phosphate-salt concentration, were independently known in the art.
Shimada thus confirms two things directly relevant to claim 1: first, that TTCP particle size (the same variable recited in claim 1 step (iii) as "2 µm to 20 µm") is a recognized (abstract, and page 234 ¶ 2. Materials and Methods) result-effective variable for controlling CPC setting time, consistent with Khairoun ’243's general teaching that setting time depends on the particle sizes of the powder components (¶ 0065); and second, that CPC setting times at and above 60 minutes, extending toward the claimed 60-120 minute range, were achievable and had already been reported in the CPC art using the same class of variables (phosphate-salt concentration, TTCP particle size) that Khairoun ’243 and Khairoun ’97a/’97b identify as the controlling parameters of setting behavior in Na₂HPO₄-accelerated cements. Selecting a Tf of 60-120 minutes therefore falls within the range of setting times a POSA would have expected to obtain, and would have been motivated to target, through routine adjustment of TTCP particle size and Na₂HPO₄ concentration — the optimization of recognized result-effective variables. See In re Applied Materials, 692 F.3d 1289, 1295 (Fed. Cir. 2012); In re Aller, 220 F.2d 454, 456 (CCPA 1955).
F. Claim 3 — pH of 8.2 to 9.5: obviousness as routine optimization of a result-effective variable
Claim 3 recites that the Na₂HPO₄ solution of claim 1 has a pH of 8.2 to 9.5 and is a 2.5% to 4% solution. Khairoun ’243 discloses a Na₂HPO₄ liquid phase with a preferred pH of "between 5 to 10, preferably between 5 and 9, most preferably between 5 and 7" (¶ 0063) and a concentration of "2 to 3% by weight" (¶ 0062), which overlaps the low end of the claimed 2.5-4% concentration range and falls within the outer bound (5-10) and the "preferably" bound (5-9) of Khairoun ’243's disclosed pH range. While Khairoun ’243's most-preferred pH (5-7) does not itself reach the claimed 8.2-9.5 range, pH of a Na₂HPO₄ solution is not an independently and arbitrarily selected parameter separate from concentration; it is a direct, well-understood physicochemical consequence of Na₂HPO₄ concentration and of the presence of other basic or acidic species in solution, a relationship that was well known to a POSA formulating CPC liquids as of the effective filing date. Khairoun ’243 itself discloses that a POSA routinely adjusts the liquid-phase composition, including through use of NaOH or other pH-modifying agents in combination with Na₂HPO₄ (¶ 0067), to achieve a targeted setting behavior, confirming that pH within the broader 5-10 disclosed range is itself a parameter that a POSA would routinely tune, and not a fixed, unalterable property of the Na₂HPO₄ liquid.
It would have been obvious to a POSA to select a pH within the 8.2-9.5 range, which sits within Khairoun ’243's own disclosed outer range of "5 to 10" and its "preferably" range of "5 and 9" (overlapping the claimed range from 8.2 to 9.0), because: (1) Khairoun ’243 itself identifies 5-10 as the operative pH range for the very same Na₂HPO₄ CPC liquid phase relied upon in the rejection, such that a pH of 8.2-9.5 is not extrinsic to the disclosed range but falls at the upper end of a range Khairoun ’243 itself identifies as workable; (2) a POSA seeking to lengthen the setting time of the cement toward the claimed 60-120 minute Tf (see Section E, above) would have been motivated to select a more alkaline pH within Khairoun ’243's own disclosed 5-10 range, because higher pH reduces the solubility and dissolution rate of the acidic calcium phosphate reactants (MCPM, brushite), consistent with the general CPC solubility relationship on which Khairoun ’243's own teachings and Shimada's teachings depend, and thereby predictably slows the setting reaction; and (3) pH selection within a disclosed operative range, for the purpose of achieving a resulting property (here, setting time) that varies predictably with that parameter, is the optimization of a result-effective variable and is prima facie obvious. See In re Applied Materials, 692 F.3d 1289, 1295 (Fed. Cir. 2012) ("[W]here the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art"); In re Aller, 220 F.2d 454, 456 (CCPA 1955); KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007) (a combination of familiar elements according to known methods, yielding predictable results, is likely obvious). Applicant has not identified, and the specification does not appear to demonstrate, any unexpected result specifically attributable to the 8.2-9.5 pH sub-range as distinct from the broader 5-10 range already disclosed in Khairoun ’243, nor any criticality of this specific sub-range independent of the concentration and setting-time parameters separately addressed above.
G. Claim-by-claim application
Regarding claim 1: Step (i) is rendered obvious by Ni (nacre is a reactive CaCO₃/aragonite biomineral), Chen (CaCO₃ + MCPM + phosphate-containing liquid → brushite, confirming the reaction proceeds with undemineralized CaCO₃ generally), and Khairoun ’243 (MCPM as a preferred CPC component, ¶ 0049). The recitation that ground nacre has a particle size of 200 µm or less is disclosed by Ni, which uses nacre powder of particle size ≤100 µm (Materials and Methods), within the claimed range, and is additionally a routine result-effective variable per Khairoun ’243 ¶ 0065 and ¶ 0098 (particle size control of CPC powders by grinding/sieving). The recitation that the reaction produces "unreacted ground nacre" as a co-product follows from the incomplete-conversion chemistry disclosed in Ni, in which the bulk of the nacre remains unconverted aragonite even after extended exposure (Ni, Discussion, p. 4328), such that a POSA controlling reaction time/stoichiometry to leave a fraction of unreacted nacre — for the disclosed and predictable purpose of retaining nacre's bioactive/osteoinductive matrix, per Simon ¶ 0021 and Ni's own teachings regarding nacre's osteoinductive proteins — would have arrived at this limitation through routine adjustment of known, result-effective reaction parameters.
Step (ii) (grinding brushite to ≤ 30 µm) is rendered obvious by Khairoun ’243 ¶ 0065 and ¶ 0098 (particle size of CPC powder components, including α-TCP ground to 0.1-80 µm, controls setting time and reactivity) and by Shimada (TTCP and DCPA particle size distributions, in the low single-digit to tens-of-microns range, significantly affect CPC setting behavior). Selection of a particle size of 30 µm or less for brushite is the optimization of a recognized result-effective variable within ranges already practiced in the art.
Step (iii) is rendered obvious by the combination as follows: Simon and Khairoun ’243 disclose TTCP as a known CPC component (Simon ¶ 0028; Khairoun ’243 ¶ 0049); Shimada discloses that TTCP particle size (including sizes as low as 5 µm, within the claimed 2-20 µm range) is a result-effective variable controlling setting time and HA/apatite formation; Khairoun ’243 ¶ 0062, ¶ 0091, and ¶ 0104 disclose Na₂HPO₄ solution as the CPC setting liquid; Simon ¶ 0043 and Khairoun ’243 ¶ 0071/claim 23 disclose the recited bioactive/therapeutic agents (antibiotics, anti-inflammatory agents, growth factors, BMPs including BMP-2); and Lee confirms that carbonate apatite is a known reaction product of CaCO₃-bearing calcium phosphate systems reacted in a sodium phosphate solution. The final setting time of 60-120 minutes is addressed in Section E above via Shimada and Khairoun ’243. Each element of step (iii) is therefore taught or rendered obvious, and their combination in a single composition and process is the combination of known elements according to known methods to achieve a predictable result.
Regarding claim 2: The 4:10 weight-to-weight ratio of nacre to MCP is a result-effective variable governing reaction stoichiometry and conversion yield, routinely optimized by a POSA per Khairoun ’243 ¶ 0065 and Simon ¶¶ 0023-0028. Obvious over the base combination for the reasons previously set forth and carried forward.
Regarding claim 3: Addressed in Section F above.
Regarding claims 7-8: Use of the composition for repair of a calcified tissue (tooth or bone) is disclosed by Ni (dental/orthopedic bone repair), Simon (claims 38, 44), and Khairoun ’243 (claims 24, 26-27). Obvious over the combination for the reasons previously set forth and carried forward.
Regarding claim 16 (set at 100% humidity and 37°C): These are standard physiological/in vitro incubation conditions for CPC setting, disclosed as routine in Khairoun ’243 (Examples, e.g., ¶ 0129-0139, samples stored in saline at 37°C) and consistent with Shimada's and Chen's use of physiological-temperature setting environments. Obvious as the routine application of known incubation conditions.
Regarding claim 17 (peak load > 45 N or compressive strength > 2.3 MPa): The mechanical properties of the composition flow directly and predictably from the claimed composition and manufacturing process, which is rendered obvious for the reasons set forth above; a difference in degree of a property that flows naturally from an obvious composition does not by itself establish nonobviousness. Applicant's asserted unexpected results are separately addressed below.
Regarding claim 18 (implantable or injectable): Disclosed by Simon (¶ 0022) and Khairoun ’243 (claim 22, "being injectable"; ¶ 0069). Obvious over the combination.
Regarding claim 19 (initial setting time (Ti) of 30-90 min): Rendered obvious for the same reasons set forth in Section E above with respect to the final setting time (Tf) of claim 1, as Ti and Tf are both controlled by the same result-effective variables (TTCP particle size, phosphate-salt concentration, pH) disclosed in Khairoun ’243 and Shimada, and Shimada's disclosed setting-time range (4.3-68 min) spans and overlaps the claimed 30-90 min Ti range.
Regarding claim 20 (temperature combinations for the two reaction stages): Room temperature and 37°C (physiological temperature) are the two standard, art-recognized temperature conditions for CPC processing and in vivo/in vitro simulation, as disclosed throughout Khairoun ’243 (room temperature mixing; 37°C incubation, e.g., ¶¶ 0093, 0131) and Chen/Shimada. Selection of one or the other, or both, for either reaction stage is the routine application of known, art-standard processing temperatures, and each of subparts (i)-(viii) is an obvious permutation of these two known temperature conditions.
Regarding claim 21 (drying the brushite before grinding): Drying a wet-precipitated calcium phosphate reaction product before subsequent grinding/sieving is a routine, art-standard processing step (see, e.g., Khairoun ’243 ¶ 0098, describing crushing and milling of a precipitated calcium phosphate product). Obvious as routine processing.
Regarding claim 22 (separating ground brushite so that all particles have a particle size of 10 µm to 30 µm): A narrower selection within the particle-size range already addressed in claim 1 step (ii) and Section G above; obvious as the optimization of a result-effective variable and as routine particle-size classification (sieving), consistent with Khairoun ’243 ¶ 0098.
Response to Arguments – Secondary Considerations
Applicant argues that Table 3 (mechanical data), Figures 5-9 (in vitro biological data), and Figures 11-17 (in vivo data) constitute objective evidence of nonobviousness. The Examiner has considered this evidence under Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966), and finds it insufficient to overcome the strong prima facie case of obviousness set forth above, for the following reasons.
First, as to the mechanical data of Table 3/Figure 2: Applicant compares the claimed substitute to a single porous commercial product (SKELITE™). A showing of superiority over one commercial embodiment does not establish that the results are unexpected relative to the closest prior art of record, i.e., the nacre-brushite-TTCP-Na₂HPO₄ combination taught by Ni, Simon, Khairoun ’243, Khairoun ’97a/’97b, Chen, Shimada, and Lee. No side-by-side comparative data against a composition falling within the scope of the cited combination has been presented, and unexpected results must be commensurate in scope with, and compared against, the closest prior art rather than an unrelated commercial product. See MPEP § 716.02(e).
Second, as to the biological and in vivo data of Figures 5-17: this data compares the claimed substitute to hydroxyapatite controls. Given that Ni, Khairoun ’243, and Simon each independently establish that nacre is a recognized osteoinductive material with bone-bonding affinity superior in certain respects to synthetic hydroxyapatite (Ni, Introduction; Simon ¶ 0021, ¶ 0065), superior biological performance relative to a hydroxyapatite control is consistent with, and predictable from, nacre's already-recognized osteoinductive properties as taught in the cited art, rather than an unexpected result flowing specifically from the particle-size, agent, and setting-time limitations added by amendment.
Third, Applicant's evidence, while acknowledged, does not overcome the strong prima facie case of obviousness established above, particularly in view of the multiple independent references now confirming that each individual claimed element and their combination were known, result-effective, and predictably combinable by a POSA.
Response to Remaining Arguments
Applicant's remaining arguments regarding the individual characterization of Ni, Simon, and Khairoun ’243 (e.g., that Ni alone does not disclose a manufacturing process, that Ni's chemistry differs in reagents and timescale from claim 1 step (i) considered in isolation) are acknowledged, but do not overcome the rejection because the rejection has never rested on Ni, Simon, or Khairoun ’243 individually disclosing every element; rather, it rests on the combination of Ni, Simon, Khairoun ’243, Khairoun ’97a, Khairoun ’97b, Chen, Shimada, and Lee, each supplying a specific teaching as mapped in Sections A-G above. Applicant's characterization of Khairoun ’243 ¶ 0068 as teaching that CaCO₃ functions solely as a setting retarder is addressed and rebutted in Section B above by Khairoun ’97a and ’97b. Applicant's characterization of Simon's nacre as exclusively demineralized and therefore chemically incapable of the claimed reactive chemistry is addressed and rebutted in Section C above by Chen. Applicant's argument regarding the non-overlap of Khairoun ’243's disclosed setting time with the claimed Tf of 60-120 minutes is addressed and rebutted in Section E above by Shimada. Applicant's argument that Khairoun ’243 does not disclose TTCP particle size in a nacre-brushite system is addressed in Sections E and G above by Shimada. Applicant's argument regarding the absence of a carbonate apatite teaching is addressed in Section D above by Lee.
Conclusion
No claims are 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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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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