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 the Claims
The amended claims filed on June 17, 2026 are acknowledged. Claims 1 and 32 have been amended to incorporate limitations of previously dependent claim 11. Claims 9, 12, and 30-31 have been amended. Claims 10- 11, 21, and 26-27 have been canceled. Claims 3, 5, 8, 13-14, 16-17, 19-20, and 22 were previously canceled.
Claims 1-2, 4, 6-7, 9, 12, 15, 18, 23-25, and 28-32 are pending and examined on the merits.
Priority
Applicant has canceled claims 10-11, 21, and 26-27 which were previously granted a priority date of the instant filing, July 29, 2022. Applicant claims domestic priority from U.S. provisional application 63/228,411 filed on August 2, 2021. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1-2, 4, 6-7, 9, 12, 15, 18, 23-25, 28-32 and are entitled to the benefit of U.S. provisional application 63/228,411 and are given an effective filing date of August 2, 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on July 29, 2022 and October 27, 2022 are in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Interpretation
It was previously noted in the office action dated March 17, 2026 that Applicant’s claims do not specifically define what is to be considered the osteoinductive composition of the instant invention. As such, the broadest reasonable interpretation of the instant osteoinductive composition is considered to be the proteins, including osteogenic bone morphogenic proteins (BMPs), extracted from bone tissue during demineralization which can be further isolated and processed into osteoinductive implants/devices. Previously dependent (presently canceled) claim 11 recited limitations that the osteoinductive composition produced by the method of claim 1 could further comprise collagen, bone mineral, and/or DBM (demineralized bone matrix). Applicant has amended claims 1 and 32 to incorporate the limitation from previously dependent claim 11 reciting that the osteoinductive composition “comprises DBM” and has canceled claim 11. Applicant’s specification supports embodiments where the osteoinductive composition can “further comprise” collagen and/or DBM (Para. [0016], [0026]) and states that one or more active ingredients, including DBM, may be added to the resulting osteoinductive composition (Para. [00153]) as well as that the osteoinductive composition can be combined with one or more thickening materials, which can be DBM (Para. [00154], [00157], see also Paras. [00158], [00161]). Therefore, one having ordinary skill in the art would understand that the scope of the osteoinductive composition of the instant invention encompasses embodiments where native bone proteins extracted from bone tissue during demineralization (e.g., BMPs) could be recombined with a matrix or carrier, e.g. DBM, order to form an osteoinductive composition comprising DBM and extracted native bone proteins.
Further, Applicant has amended claims 1 and 32 to recite osteoinductive compositions which comprise DBM but has not amended claim 12 in a similar manner, which serves to support the interpretation of an embodiment where the osteoinductive composition does not comprise DBM and is considered to be native bone proteins extracted from bone during demineralization and which can be added to a matrix of DBM.
Maintained Claim Rejections - 35 USC § 112
Claim 12 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Dependent claims have been included in the rejection as they do not clarify the scope of the claims.
Claim 12 recites the limitations “native bone proteins” in lines 5 and 10 as well as "a bone protein" in line 12. As claimed, it is unclear whether “a bone protein” is intended to refer to the same proteins as the previously recited “native bone proteins” which are exposed via the method steps or whether the claims are intended to encompass different subsets of bone proteins, thus rendering the claim indefinite. Appropriate correction is required. It is recommended that Applicant amend the claim language to refer to “native bone proteins” for clarity.
New Claim Rejections - 35 USC § 103
Claims 1-2, 4, 6, 7, 9, 12, 15, 18, 24-25, 28, and 31-32 are rejected under 35 U.S.C. 103 as being unpatentable over Thorne (US 20070049731) in view of Urist (US 4,294,753) and McKay (US 9,364,583).
This is a new rejection necessitated by Applicant’s amendment. This rejection shares substantial similarity to the rejection as set forth in the previous office action dated March 17, 2026. The following new rejection provides additional interpretation of the claims which is necessitated by Applicant’s amendment in the response filed June 17, 2026. Any aspect of Applicant’s traversal that pertains to the rejection as newly set forth will be provided following the new statement of rejection.
With regard to claims 1 and 12, Thorne teaches a method of obtaining osteoinductive proteins for use in osteoinductive devices (Para. [0002]) from bone tissue (Para. [0029], lines 1-2) which is first cleaned by washing and soaking (Para. [0030], lines 5 & 7) and subsequently demineralized to extract the bone morphogenetic proteins (BMPs) by soaking in a solution of a “suitable acid” (Para. [0020], Para. [0032]). Thorne further teaches the acid-based demineralization solution may contain additives that enhance solubility such as calcium chloride (a salt) or “other organic solvents in which minerals are soluble” (Para. [0034], lines 3-6). Thorne teaches that the resultant end product containing bone-derived osteoinductive proteins can be lyophilized (Para. [0023], line 11; Para [0049], lines 1-3) in preparation for use as an osteoinductive composition.
While Thorne teaches a bone demineralization method comprising the mixture of acid and salt, Thorne is silent as to salt concentration in the bone demineralization solution. However, Thorne does cite Urist as teaching a bone demineralization method comprising the use of acid and salt (Para. [0004]).
Urist teaches a method for separating bone morphological proteins (BMPs) by demineralization of bone tissue for use as an osteoinductive implant (Col. 2, lines 62-66). Bone tissue is crushed and cleaned (Col. 2, line 68) then demineralized by soaking in hydrochloric acid (Col 3. line 2). As a second step, bone tissue is soaked in a solution containing a “neutral salt” such as calcium chloride (Col. 3, lines 14-17) at a concentration of about 0.5M (Col. 8, line 15, claim 16) or “high concentration” of other salts such as sodium chloride (Col. 4, lines 1-4). Urist further teaches that extracted BMPs can be mixed with calcium phosphate to be used as an implantable osteoinductive material (Col. 3, lines 38-42) and that the BMP-containing end product can be lyophilized (Col. 5, line 40).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to apply the about 0.5M salt concentration taught by Urist to Thorne’s method of demineralization using a solution of an acid comprising a salt. Both Urist and Thorne teach that use of a salt during demineralization can improve protein solubility. Since Urist teaches a salt concentration of about 0.5M, one of ordinary skill in the art would be motivated to apply the salt concentration as taught by Urist for use in the demineralization solution of acid comprising a salt as taught by Thorne. One of ordinary skill in the art would have had a reasonable expectation of success as both Thorne and Urist teach methods of bone demineralization comprising use of an acid and salt in order to produce BMP-containing osteoinductive compositions. Further, as Thorne and Urist both teach that addition of salt increases osteoinductive protein solubility (Thorne Para. [0034]), Urist Col. 3, lines 16-19), a skilled artisan would recognize that an osteoinductive composition generated by demineralization using an acid solution containing a salt would contain increased BMP concentration when compared to an osteoinductive composition generated by demineralization using an acid solution without a salt.
Further, although Thorne does not teach a salt concentration, it would have been within the ambit of one with ordinary skill in the art to adjust the concentration of salt in the acid-based bone demineralization solution through routine optimization. See MPEP 2144.05(II)(A) which states:
“Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”
Both Thorne and Urist teach that use of a salt can improve protein solubility during bone demineralization using an acid solution. Urist teaches that a salt concentration of about 0.5M is known to be effective in enhancing protein solubility during bone demineralization using an acid. Adjustments of working concentrations to determine optimum values or ranges are a common technique well known in the art. Therefore, one of ordinary skill in the art would have recognized that routine experimentation using different salt concentrations in an acid-based bone demineralization solution might lead to changes or improvements in protein solubility. One of ordinary skill in the art would have had a reasonable expectation of success since use of a salt is known to improve protein solubility during bone demineralization using an acid solution.
Thorne teaches that the extracted BMP mixture can be combined with a matrix in order to form an osteogenic implant (Para. [0027]) and that the demineralized bone (i.e., “demineralized and devitalized bone matrix”) can be used as a matrix for delivery of the extracted osteoinductive proteins (Para. [0063], lines 14-15), this is considered to reasonably read on an osteoinductive composition comprising DBM. Further, Thorne teaches use of high molecular weight ultrafiltration to eliminate bacteria and microorganisms to ensure a sterile product and that ultrafiltration using pore sizes smaller than bacteria permit sterilization by filtration (Para. [0044], lines 9-12). Thus, Thorne provides support for combining the extracted BMP mixture with DBM in order to form an osteoinductive implant and for a sterilization step in the method of producing an osteoinductive composition.
Neither Thorne nor Urist teach sterilization of the demineralized bone matrix.
McKay teaches an osteoinductive demineralized bone implant comprising demineralized bone matrix (DBM) and methods of making the osteoinductive implant (Abstract). McKay teaches that the DBM for use in the implant includes the collagen matrix, BMPs, and other growth factors (Col. 10, lines 21-23) and exhibits osteoinductive potential (Col. 10, lines 29-30). McKay teaches that the osteoinductive implant can further comprise BMPs (Col. 16, lines 10-13). Similar to the teachings of Thorne and Urist, McKay teaches a lyophilization step of the DBM for storage (Col. 11, lines 30-33). Additionally, McKay teaches that teaches that the osteoinductive implant may be sterilized by radiation (Col. 26, line 28) in order to provide a greater assurance of sterility (Col. 26, line 30) as compared to other sterilization procedures.
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to apply sterilization of the demineralized bone using radiation as taught by McKay to the osteoinductive device comprising extracted osteoinductive BMPs and a matrix of demineralized bone as taught by Thorne with a reasonable expectation of success as both Thorne and McKay teach production of osteogenic implants from bone tissue. A skilled artisan would have been motivated to apply sterilization of the demineralized bone tissue using radiation because McKay teaches that use of radiation provides increased sterilization, which a skilled artisan would recognize is critical for products intended to be implanted into a subject.
With regard to claim 2, Thorne teaches that the bone starting product may be cortical, cancellous, or corticocancellous bone (Para. [0029], lines 6-7).
With regard to claims 4 and 15, as detailed above, Urist teaches that the salt concentration is about 0.5M (Col. 8, line 15, claim 16).
With regard to claim 6, Thorne teaches a method of exposing BMPs and “other tissue-inductive proteins” (Para. 0002) which are further defined as including BMP-1 through BMP-18, members of the transforming growth factor beta (TGF-beta) family (Para. 0003, lines 7-13), non-collagenous bone proteins (Para. 0040, line 10), and osteoinductive protein-containing collagen (Para. 0058, lines 7-9).
With regard to claim 7, Thorne teaches the acid-based demineralization solution may contain additives such as calcium chloride, a salt (Para. [0034]).
With regard to claims 9 and 18, Thorne teaches use of hydrochloric acid for bone demineralization (Para. [0032]) and that the demineralization solution comprising hydrochloric acid may comprise additives such as calcium chloride (Para. [0034]).
With regard to claim 24, as detailed above, Thorne teaches that the osteoinductive BMP composition can be lyophilized (Para. [0023], line 11; Para [0049], lines 1-3) for storage which is considered to reasonably read on comprising a moisture content of less than 6% by weight as one of ordinary skill in the art would recognize that lyophilization of a composition for longer-term storage would require removal of as much moisture as possible, which is considered to reasonably read on less than 6% by weight.
With regard to claim 25, Urist teaches a two-step bone demineralization process wherein bone particles are mixed with “ice cold” hydrochloric acid (Col. 5, line 6) and subsequently mixed with a “cold aqueous solution of a neutral salt” (Col. 3, lines 14-15) in order expose BMPs. Although Urist is silent to the specific temperature of the acid used in the method, it would be well-known to one having ordinary skill in the art that about 4° C is the generally accepted temperature for laboratory reactions which occur on ice or in an ice-cold solution. Additionally, Urist teaches that it is preferable to carry out BMP solubilization steps at a temperature range of 2°-5° C and that reduced temperatures decrease the chances of protein denaturation (Col. 4, lines 14-15). This is considered to read on using a demineralization solution at about 4° C.
Independently, optimization of reaction temperature is a common laboratory technique known to those skilled in the art. Thorne teaches bone demineralization at temperatures from “about room temperature” to 37° C (Para. [0036]). However, one having ordinary skill in the art could have easily envisioned performing bone demineralization at 4° C, particularly in view of Urist’s teaching that cold temperatures help to maintain proper protein conformation. See MPEP 2144.05(II)(A) as recited above. One having ordinary skill in the art would recognize that proper protein conformation is critical for protein function and thus, would be motivated to perform bone demineralization at 4° C in order to yield an osteoinductive composition comprising proteins maintained in native conformation thereby maintaining osteoinductive potential.
With regard to claim 28, Thorne teaches that demineralization by soaking in acid may take 1-2 hours (Para. [0057], line 8), which is considered to reasonably read on 60-90 minutes.
With regard to claim 31, as detailed above, Urist teaches that the salt could be sodium chloride, i.e., NaCl (Col. 4, lines 1-4, claim 7).
With regard to claim 32, as detailed above, the combination of Thorne, Urist, and McKay teach a method of producing an osteoinductive composition comprising obtaining bone tissue, washing the bone tissue, demineralizing the bone tissue in order to expose BMPs by soaking the bone tissue in an acid solution containing a salt which generates an osteoinductive composition having increased BMP concentration compared to an osteoinductive composition demineralized in an acid solution without a salt. Urist teaches that the salt can be 0.5M calcium chloride or that a “high concentration” of sodium chloride could also be used. Thorne additionally teaches that devitalized and demineralized bone matrix can be combined with the osteoinductive BMP composition in order to be used as an implant, which is considered to reasonably read on an osteoinductive composition comprising DBM, and McKay teaches that osteoinductive implants made from demineralized bone matrix can be sterilized with radiation.
The combination of Thorne, Urist, and McKay is silent as to the specific concentration of sodium chloride.
Since Urist teaches that, as an alternative to 0.5M calcium chloride, a “high concentration” of sodium chloride (Col. 4, lines 19-22) could be used in demineralization of bone tissue in order to generate a BMP comprising osteoinductive composition, a skilled artisan would reasonably assume that the concentration of sodium chloride would be greater than 0.5M. Adjustments of working concentrations to determine optimum values or ranges are a common technique well known in the art (See MPEP 2144.05(II)(A)). Therefore, one of ordinary skill in the art could have easily arrived at a sodium chloride concentration of 1M via routine optimization using different salt concentrations in an acid-based bone demineralization solution in order to find a concentration of sodium chloride which effectively improved protein solubility during acid demineralization. Additionally, one of ordinary skill in the art would have been limited to a finite number of sodium chloride concentrations which were greater than 0.5M but lower than the saturation point for sodium chloride solution. Further, a skilled artisan would have been motivated to use the lowest sodium chloride concentration which improved protein solubility possible as a high concentrations of salt would be more difficult to remove from the BMP containing osteoinductive composition prior to use as an osteogenic implant. One of ordinary skill in the art would have had a reasonable expectation of success since both Thorne and Urist teach that use of a salt is known to improve protein solubility during bone demineralization using an acid solution and Urist teaches that sodium chloride can be used for bone demineralization and BMP extraction.
Claims 23 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Thorne, Urist, and McKay as applied to claim 1 in further view of Lee et al. (US 20220378980, US version of WO2021085775 found in IDS dated 10/27/2022, hereafter “Lee”).
With regard to claim 23, as detailed above and incorporated herein, the combination of Thorne, Urist, and McKay teach a method of producing an osteoinductive composition comprising obtaining bone tissue, washing the bone tissue, demineralizing the bone tissue in order to expose BMPs by soaking the bone tissue in an acid solution containing a salt having a concentration of 0.5M which generates an osteoinductive composition having increased BMP concentration compared to an osteoinductive composition demineralized in an acid solution without a salt. Thorne additionally teaches that the demineralized bone tissue can be combined with the osteoinductive BMP composition in order to be used as an implant and McKay teaches that osteoinductive implants made from devitalized and demineralized bone matrix can be sterilized with radiation.
Urist teaches the volume ratio of the demineralization solution can be 1 part bone particles to 10 parts hydrochloric acid or that “volumes up to about 100 parts” may be used (Col. 5, lines 9-11). Thus, Urist provides support for adjustment of the ratio of acid solution to bone during demineralization which could be done via routine optimization. However, Urist does not specifically teach wherein the acid solution comprising salt is combined by about 40 mL of the acid-salt solution per gram of the bone tissue.
Lee teaches a method of producing demineralized bone matrix composition comprising demineralizing bone tissue with an acid solution (Para. [0020], [0039]) and extracting BMP-2 (Para. [0023], [0041]) in order to generate a composite DBM composition comprising the demineralized bone tissue and BMP-2 (Para. [0024], [0042]) used for bone grafting (Para. [0026]), which is considered to reasonably read on an osteoinductive composition. Lee teaches that bone tissue may be washed (Para. [0053], lines 1-2) prior to demineralization with an acidic solution (Para. [0054], lines 2-3), that the type of acid used is “not particularly limited” (Para. [0058], lines 1-2), and that the concentration and content of the acidic solution may be suitably selected according to the acid type (Para. [0059]). Further, Lee teaches an embodiment wherein the demineralization of bone can be performed with 10 to 50 mLs of hydrochloric solution per 1 g of bone tissue (Para. [0060]).
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to choose the ratio of hydrochloric acid to bone for demineralization as taught by Lee for use in the method of demineralization of bone in an acid solution containing a salt as taught by the combination of Thorne and Urist in order to arrive at the instantly claimed concentration of about 40mL of acid solution per gram of bone with a reasonable expectation of success. A skilled artisan would have been motivated to choose the ratio as taught by Lee because both Urist and Lee teach that the concentration of acid per gram of bone tissue used for demineralization can be adjusted via routine optimization. As both Urist and Lee teach a starting ratio of 10 mL of acid per gram of bone tissue and Lee teaches a range comprising 10 mL to 50 mL of hydrochloric acid per gram of bone tissue which comprises a finite number of volumes of hydrochloric acid, a skilled artisan could have readily arrived at the instantly claimed concentration via routine optimization in order to select the hydrochloric acid to bone ratio which is most effective at extracting BMPs from bone tissue for further processing and use in a BMP-comprising osteoinductive composition.
With regard to claim 30, as detailed above in claim 1, McKay teaches that the osteoinductive implant may be sterilized by radiation (Col. 26, line 28) including electron beam radiation (Col. 26, lines 1-3). However, McKay is silent as to the specific dose of radiation.
Lee teaches a method of producing demineralized bone matrix composition comprising demineralizing bone tissue with an acid solution (Para. [0020], [0039]) and extracting BMP-2 (Para. [0023], [0041]) in order to generate a composite DBM composition comprising the demineralized bone tissue and BMP-2 (Para. [0024], [0042]) which can be used for bone grafting (Para. [0026]), which is considered to reasonably read on an osteoinductive composition. Lee further teaches that the composition can be sterilized (Para. [0132]) in order to eliminate immunity from the bone tissue composition and kill bacteria (Para. [0133]) and that sterilization may be performed by irradiation at a range of 10 to 30 kGy (Para. [0134]).
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to choose the irradiation range of 10 to 30 kGy as taught by Lee for use in the method of producing an osteoinductive composition which can be combined with a demineralized bone tissue matrix which has been sterilized by electron beam radiation as taught by the combination of Thorne, Urist, and McKay with a reasonable expectation of success as both McKay and Lee teach sterilization using irradiation. Lee teaches that doses of irradiation at 10 to 30 kGy are effective at eliminating immunity from bone tissue and killing bacteria, thus a skilled artisan would have recognized that the irradiation dose as taught by Lee would be effective for sterilizing the implant and to avoid deleterious effects of immune reactions, both of which are critical for compositions which are intended for implantation.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Thorne, Urist, McKay, and Lee as applied to claims 1 and 23 and in further view of Pietrzak et al. (2011, BMP depletion occurs during prolonged acid demineralization of bone: characterization and implications for graft preparation. Cell and Tissue Banking, 12(2), 81-88, hereafter “Pietrzak”) and Urist (1965, Bone: Formation by Autoinduction. Science, 150(3698), 893-899, hereafter “Urist (1965)”).
With regard to claim 29, as detailed above and incorporated herein, the combination of Thorne, Urist, and McKay teach a method of producing an osteoinductive composition comprising obtaining bone tissue, washing the bone tissue, demineralizing the bone tissue in order to expose BMPs by soaking the bone tissue in an acid solution containing a salt having a concentration of 0.5M which generates an osteoinductive composition having increased BMP concentration compared to an osteoinductive composition demineralized in an acid solution without a salt. Thorne additionally teaches that the demineralized bone tissue can be combined with the osteogenic BMP-containing composition in order to be used as an implant. McKay teaches that osteoinductive implants made from demineralized bone tissue can be sterilized with radiation. Lee teaches that the acid solution can be combined with bone at a ratio of about 40mLs of the acid solution per gram of bone tissue.
The prior art of Thorne, Urist, McKay, and Lee all teach various acid concentrations, temperatures, and lengths of demineralization cycles. Thorne teaches demineralization using 2N hydrochloric acid at temperatures from room temperature to 37° C for three hours (Para. [0036]). Urist teaches demineralization in ice cold 0.6N hydrochloric acid for 24 hours (Col. 5, lines 13-15). Therefore, a skilled artisan would recognize that the demineralization cycle parameters could be optimized. In fact, McKay teaches that demineralization can be controlled by adjusting the treatment time, temperature, and concentration of demineralizing solution (Col. 9, lines 48-52).
Pietrzak teaches evaluation of demineralization time on the BMP-7 content and osteoinductive capacity in bone tissue demineralized in hydrochloric acid (Abstract). Pietrzak teaches that demineralization times of 24 hours in hydrochloric acid reduce the amount of BMP-7 remining in the demineralized bone tissue (Table 3 and Fig. 3) and that this is likely due to diffusion of BMP-7 into the acid demineralization solution (Pg. 86, left col., 2nd para.). Pietrzak further teaches that timelines of several days have been used for demineralization of bone tissue and that BMPs are stable during longer demineralization cycles.
Pietrzak is silent as to the definition of “several days”, but does cite Urist (1965) as an example of demineralization of bone tissue over several days.
Urist (1965) teaches demineralization of bone tissue in hydrochloric acid for a period of 5 days (Pg. 893, left col., last para.).
Therefore it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to apply demineralization of bone in hydrochloric acid for a period several days as taught by Pietrzak to the method of producing an osteoinductive composition by demineralizing bone by soaking in hydrochloric acid as taught by the combination of Thorne, Urist, McKay, and Lee with a reasonable expectation of success as Pietrzak, Thorne, Urist, McKay, and Lee all teach generation of osteoinductive compositions comprising extracted BMPs and bone tissue demineralized in hydrochloric acid. A skilled artisan would be motivated to apply demineralization for a period of several days as Pietrzak teaches that longer demineralization periods result in increased release of BMPs (i.e., osteoinductive agents) into the demineralization solution without negative effects on the BMPs. Further, a skilled artisan would be likely to use the demineralization period of 5 days as taught by Urist (1965) since Pietrzak cites Urist (1965) as an example of demineralization of bone tissue over several days, particularly if a skilled artisan where choosing demineralization at cold temperatures or with weak or less concentrated acid solutions.
Response to Arguments
Applicant's arguments filed June 17, 2026 are acknowledged and have been fully considered but they are not persuasive.
Claims 1-4, 4, 6-7, 9-12, 15, 18, 21, 24-26, 28, and 31-32 were rejected under 35 U.S.C. 103 over Thorne in view of Urist and McKay. Claims 23 and 30 were rejected under 35 U.S.C. 103 over Thorne in view of Urist and McKay and in further view of Lee. Claim 29 was rejected under 35 U.S.C. 103 over Thorne in view of Urist, McKay, and Lee and in further view of Pietrzak and Urist 1965.
Claims 10-11, 21, and 26-27 have been canceled rendering the response to rejections moots. Applicant traverses the remaining rejections.
First, Applicant asserts on Pg. 10 that the applied prior art does not disclose, teach, or suggest each limitation of the rejected claims in light of Applicant’s amendments. Specifically, Applicant asserts that the combination of Thorne, Urist, and McKay do not teach the instantly claimed osteoinductive composition. Applicant traverses the Office’s interpretation of an osteoinductive composition which is native bone proteins extracted during demineralization of bone tissue to form DBM in light of the amendments to claims 1 and 32 to recite an “osteoinductive composition comprising DBM” and an “osteoinductive composition comprising DBM having a native bone protein concentration…”. Applicant asserts on Pg. 11 (1st para.) that the claims as amended produce an osteoinductive composition which “includes DBM with a native bone protein concentration comparatively greater than bone tissue soaked in deionized water acid solution” and that the osteoinductive composition includes DBM and native bone proteins remaining on bone tissue, not extracted as taught by the prior art of Thorne and Urist. Applicant asserts on Pg. 11 (2nd para.) that the instantly claimed method steps of claims 1 and 32 describe an osteoinductive composition which is produced through demineralization and where native bone protein is retained on bone tissue. Applicant asserts on Pg. 11 (3rd para.) that Thorne and Urist disclose isolation and separation of BMPs (i.e., native bone proteins) and not retention and exposure of native bone proteins as instantly claimed. Applicant asserts on Pg. 12 (last para.) that the prior art of Thorne and Urist would direct a skilled artisan to extract BMPs from bone tissue and not retain BMPs on bone tissue and that Thorne and Urist disclose purified BMPs as the desired product for osteoinductive implants.
Applicant's arguments have been fully considered but they are not persuasive.
Additional interpretation of Applicant’s claims as amended have been added to the claim interpretation section above and are incorporated herein. Applicant has amended claims 1 and 32 to narrow the scope of the osteoinductive composition such that it comprises DBM, however, Applicant has not amended claim 12 to incorporate limitations that the osteoinductive composition comprises DBM. Applicant’s amendments to claim 1 and 32 to recite an osteoinductive composition comprising DBM recites limitations found in previously dependent (and presently canceled) claim 11 which recited the osteoinductive composition could “further comprise” DBM. As such, these limitations have been considered in prior office actions. Applicant’s disclosure supports embodiments where the osteoinductive composition can “further comprise” collagen and/or DBM (Para. [0016], [0026]) and states that one or more active ingredients, including DBM, may be added to the resulting osteoinductive composition (Para. [00153]) as well as that the osteoinductive composition can be combined with one or more thickening materials, which can be DBM (Para. [00154], [00157], see also Paras. [00158], [00161]). Further, Applicant’s claims include open claim language reciting a method which comprises, but is not limited to, the recited steps and osteoinductive compositions which comprise, but are not limited to, only DBM. Thus, as detailed above, the rejections rely on an embodiment of an osteoinductive composition which is considered to be proteins extracted from bone during demineralization of bone tissue in an acid containing a salt that can be combined with a matrix of DBM in order to produce an osteoinductive composition comprising DBM. As claim 12 has not been amended to include language that the osteoinductive composition comprises DBM, it would be reasonable to a skilled artisan to interpret the osteoinductive composition as not necessarily comprising DBM. For the reasons detailed above, this embodiment is rendered obvious by the combination of Thorne, Urist, and McKay.
Second, Applicant traverses on Pg. 13 that Thorne and Urist fail to disclose demineralization of bone with an acid solution containing a salt. Applicant asserts that Urist teaches use of a salt to solubilize BMPs after, not during, bone demineralization with an acid solution and that use of Urist’s salt during demineralization would be counterproductive to the claimed method as a skilled artisan would understand use of a salt would solubilize, not retain, BMPs as instantly claimed. Applicant traverses that a skilled artisan would need to modify Urist’s teachings by adding salt to the demineralization solution and utilize salt to retain bone proteins which would change the principle of operation of the prior art thus rendering the claims non obvious.
Applicant's arguments have been fully considered but they are not persuasive.
Applicant’s traversal as it pertains to the scope of claimed osteoinductive composition has been addressed above. In response to applicant's argument that Urist teaches away from the addition of salt to the demineralization solution, although Urist teaches use of a salt solution in order to solubilize BMPs subsequent to an acid demineralization step, Thorne teaches demineralization of bone tissue using an acid solution (Para. [0032]) which can comprise additives such as salts (Para. [0034], [0040]) to help with solubilization of BMPs (Para. [0040]). Urist similarly teaches that use of a salt helps to solubilize BMPs from demineralized bone. Thus, the teachings of Urist are not relied upon for addition of a salt to an acid demineralization as instantly claimed.
Third, Applicant asserts on Pg. 13-14 that the claimed osteoinductive composition produced by the method yields unexpected results. Applicant asserts that the claimed method results in enhanced osteoinductivity of demineralized bone tissue and increased bone protein concentration which is not predictable based on the prior art. Applicant asserts the provided Declaration of Dr. Walsh demonstrates that demineralization with and acid solution containing 1M NaCl results in increased levels of BMP-2 as well as osteoinductive capacity. Applicant alleges that the instantly claimed method provides distinct advantages over the method of Thorne and Urist which were not predictable. Applicant further asserts that the prior art of McKay does not cure the deficiencies of Thorne and Urist.
Applicant's arguments have been fully considered but they are not persuasive.
Applicant’s traversal as it pertains to the scope of claimed osteoinductive composition has been addressed above. With regard to Applicant’s assertion of alleged unexpected results, the prior art of Thorne and Urist are both drawn to separation of BMPs (i.e., native bone proteins) from demineralized bone matrix using an acid based solution containing a salt and both Thorne and Urist teach that use of a salt is effective for increasing the amount of osteoinductive BMPs in order to increase osteoinductive potential. Thus, a skilled artisan would expect that use of the method of Thorne and Urist would result in increased BMPs compared to BMPs extracted from bone tissue demineralized without a salt. A skilled artisan would reasonably expect increased osteoinductive capacity based on the increased number of solubilized BMPs produced by demineralization with an acid solution containing a salt. Thus, it appears that the claimed invention exhibits results that would be expected based on the teachings of the prior art. Additionally, Applicant’s alleged unexpected results are not commensurate in scope with the breadth of the claims. Claims 1 and 12 recite a large genus of salt concentrations. Dependent claim 6 recites a large genus of native proteins which can be increased and dependent claims 7, 9, and 18 recite large genuses of salts, acids, and combinations of salt and acid which result in increased bone protein concentrations, and as stated supra, Applicant’s claims do not exclude the step of adding back of the extracted native BMPs to the osteoinductive composition comprising DBM. Applicant’s alleged unexpected results are limited a single salt (NaCl) combined with a single acid (HCl) at a single concentration (1M) and measurements of a single BMP (BMP-2) that is retained in the DBM. Therefore, Applicant’s alleged unexpected results are not commensurate in scope with the invention as instantly claimed.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
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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/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631
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