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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant's submission filed on January 26, 2026 has been entered and considered. Rejections and/or objections not reiterated from the previous office action mailed August 25, 2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior office action.
Status of the Claims
The amended claims filed on January 26, 2026 are acknowledged. Claims 3, 5, 8, 13-14, 16-17, 19-20, and 22 have been canceled. Claim 9 has been amended to incorporate limitations of formerly dependent claim 8 and claim 18 has been amended to incorporate limitations of formerly dependent claim 20. Claims 10, 21, and 26-27 have been amended to correct typographical errors. Claims 28-32 have been newly added.
Claims 1-2, 4, 6-7, 9-12, 15, 18, 21, and 23-32 are pending and examined on the merits.
Priority
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, 6-8, 9, 12, 15, 18, and 23-32 are entitled to the benefit of U.S. provisional application 63/228,411 and are given an effective filing date of 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. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/228,411, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Applicant’s traversal of priority dates for claims 6 has been fully considered and is persuasive as it relates to recitation of the native bone proteins recited in claim 6. Applicant asserts that provisional application No. 63/228,411 contains reference to BMPs 1 to 15 in Para. [0125]). Priority for native bone proteins comprising BMPS 1 to 15 is granted to the date of the provisional application 63/228,411 filed on August 2, 2021.
Additionally, claims 10-11 and 21 were inadvertently granted priority to provisional Application No. 63/228,411 in the office action dated April 17, 2025. The earlier filed application does not contain support for further processing the claimed osteoinductive composition to produce a putty, gel, block, strip, sheet, wafer, shaped implant or combination thereof nor does it contain support for an osteoinductive composition further comprising carboxymethylcellulose, chitosan, collagen, bone mineral, glycerol, hyaluronic acid, hydroxyapatite, sodium alginate, tricalcium phosphate, biphasic calcium phosphate, calcium sulfate, biological glass, poloxamer 407, DBM, a reverse phase medium, a cross-linking agent, or any combination thereof. The prior-filed application also does not contain support for further processing the osteoinductive composition to produce a sponge-like material by mixing with aqueous ethanol in newly added claims 26 and 27.
Accordingly, Claims 10-11, 21, and 26-27 are entitled to the benefit of the instant application and are given the effective filing date of the instant application: July 29, 2022.
Response to Arguments regarding Priority
Applicant’s traversal regarding matters of priority filed January 26, 2026 is acknowledged and has been fully considered and is partially persuasive.
Regarding claim 6, Applicant’s traversal of priority dates for claims 6 has been fully considered and is persuasive as it relates to recitation of BMPs 1 to 15. Applicant asserts and the office agrees that provisional application No. 63/228,411 contains reference to BMPs 1 to 15 in Para. [0125]). Regarding to the remaining native bone proteins, Applicant traverses on Pg. 9 that the level of skill in the art is
relatively high and thus a skilled artisan would recognize that collagen, collagen-type proteins, and non-collagenous proteins would be released from the collagenous matrix. This is considered persuasive.
Priority for the full scope of native bone proteins comprising as recited in claim 6 is granted to the date of the provisional application 63/228,411 filed on August 2, 2021.
With regard to claims 10 and 21, Applicant asserts on Pg. 9 that support for these claims is provided in the provisional application’s description of implanting a sample and use of the demineralized bone as bone void filler, bone graft including a substitute for a bone defect, and bone fusion as well as in various implant procedures like spinal or dental implant procedures.
Applicant’s arguments have been fully considered but are not persuasive.
These statements may provide support for a shaped implant; however, this is not considered to support the full scope of instantly claimed osteoinductive forms in claims 10 and 21 comprising forms of a putty, gel, strip, sheet, wafer, shaped implant, or combination thereof. Therefore, Applicant’s arguments regarding priority for claims 10 and 21 are not considered persuasive.
With regard to claim 11, Applicant asserts on Pgs. 9-10 that the provisional application provides examples describing addition of collagenase to the demineralized bone samples in Paras. [00131] and [00135]. The addition of collagenase is not considered to be the same compound as the instantly claimed addition of collagen as recited in claim 11. Additionally, claim 11 recites a Markush group of additional compounds which the osteoinductive composition can further comprise. Therefore, Applicant’s arguments regarding priority for claim 11 are not considered persuasive.
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.
Withdrawn Claim Objections
In light of Applicant’s amendment to claim 26 in order to fix the typographical error and recite the additional method step (f) instead of (e), the objection to claim 26 has been withdrawn.
Withdrawn Claim Rejections - 35 USC § 103
In light of Applicant’s amendments to the claims, the rejection of claims 1-2, 4, 6-13, 15, 17-18, and 20-27 over Thome (US 20070049731 Al, hereafter "Thorne") in view of Urist (US 4,294,753, hereafter "Urist"), McKay (US 9,364,583, hereafter "McKay"), and Lee et al. (US 20220378980 Al, hereafter "Lee") has been withdrawn.
Objections to the Specification
The use of the terms Pluronic F127 in Para. [00154], Quantikine ELISA, R&D Systems, and Tecan in Paras. [00164] and [00168] which are a trade names or a marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
New Claim Objections
Claim 11 is objected to because of the following informalities: Claim 11 recites the abbreviation “DBM” in line 4 without defining the abbreviation. Appropriate correction is required. It is recommended that Applicant amend the claim to define DBM followed by the abbreviation in parentheses.
Claims 31 and 32 are objected to because of the following informalities: Claims 31 and 32 recite the chemical abbreviation NaCl without defining the abbreviation. Appropriate correction is required. Is it recommended that Applicant amend the claim to define the abbreviation and for consistency with other claims which recite Markush groups of salts that do not contain chemical abbreviations (e.g., claims 7, 9, and 18).
Claim Interpretation
It is noted 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. Dependent claim 11 indicates that the osteoinductive composition produced by the method of claim 1 can further comprise collagen, bone mineral, and/or DBM (demineralized bone matrix) which would indicate to one having ordinary skill in the art that the osteoinductive composition of the instant invention does not comprise any collagen, bone mineral, or DBM remaining during the demineralization process but is rather intended to refer to the extracted osteoinductive proteins which can subsequently be added to matrices such as collagen or DBM.
New Claim Rejections - 35 USC § 112
Claims 1-2, 4, 6-7, 9-12, 15, 18, 21, and 23-32 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. Dependent claims have been included in the rejection as they do not clarify the scope of the claims.
Claims 1, 12, and 32 recite the limitations “native bone proteins” in lines 5 and 10 (claims 1 and 12) and lines 4 and 9 (claim 32) as well as "a bone protein" in lines 12 (claims 1 and 12) and line 11 (claims 32). 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.
Claim 9, which depends from claim 1, recites the limitation "the acid solution" in line 5. There is insufficient antecedent basis for this limitation in the claim as prior recitations are to an acid solution containing salt. As claimed, it is unclear if the acid solution is intended to refer to the acid solution containing salt or a different acid solution. Appropriate correction is required.
Claim 32 recites the limitation “ NaCl having a concentration between about 1.0M” in line 7 which renders the claim indefinite. As claimed, it is unclear what values of NaCl concentration are intended to be included within the scope of the claim. Appropriate correction is required.
New Claim Rejections - 35 USC § 103
Claims 1-2, 4, 6, 7, 9-12, 15, 18, 21, 24-26, 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 August 25, 2025. 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 tissue can be used as a matrix for delivery of the extracted osteoinductive proteins (Para. [0063], lines 14-15). 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 demineralized bone tissue 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 with radiation.
McKay teaches an osteoinductive demineralized bone implant comprising demineralized bone matrix and methods of making the osteoinductive implant (Abstract). McKay teaches that the demineralized bone tissue 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). 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 tissue using radiation as taught by McKay to the osteoinductive device comprising extracted osteoinductive BMPs and a matrix of demineralized bone tissue 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 claims 10 and 21, Thorne teaches an osteogenic implant device used for bone repair comprising the extracted osteogenic BMP composition and a matrix (Para. [0027]) and further teaches that the osteogenic BMP composition could be added to a “solid carrier” such as collagen or bone chips (Para. [0050]). This is considered to reasonably read on a shaped implant as one of ordinary skill in the art would understand these teachings imply a structural integrity which would create a shaped implant.
With regard to claim 11,Thorne teaches that extracted osteoinductive BMPs can be combined with a solid carrier such as collagen or hydroxyapatite (Paras. [0050] and [0051]).
With regard to claim 24, 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 claims 26 and 27, as detailed above, the combination of Thorne, Urist, and McKay teach a method of making 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 thereby generating an osteoinductive composition having increased BMP concentration compared to an osteoinductive composition demineralized in an acid solution without a salt.
Although Thorne teaches that the osteoinductive composition may be added to a matrix (Para. [0027]), a solid carrier, or mixed in a liquid or slurry (Para. [0050]), Thorne is silent as to the osteoinductive composition being formed into a sponge-like material.
McKay teaches an osteoinductive demineralized bone implant comprising demineralized bone tissue which comprises a collagen matrix, BMPs, and other growth factors (Col. 10, lines 21-23) and which exhibits osteoinductive potential (Col. 10, lines 29-30). McKay further teaches that the demineralized bone tissue comprising a collagen matrix, BMPs, and other growth factors can be formulated for use as a sponge material (Col. 10, lines 23-24).
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date for the claimed invention, to choose an the sponge-like form of the osteoinductive composition comprising BMPs and a matrix as taught by McKay for use in Thorne’s osteoinductive composition comprising BMPs and a matrix which can be formulated with various viscosities and/or forms with a reasonable expectation of success as both Thorne and McKay teach osteoinductive implants comprising BMPs and demineralized bone tissue matrix which can be shaped prior to implantation. A skilled artisan would have been motivated to choose a sponge-like form in order to form osteoinductive implants having pores which would allow endogenous fluids and proteins to penetrate the implant and endogenous cells to infiltrate and proliferate which would be likely to increase the success of the implant.
Regarding the method of making the osteoinductive implant comprising BMPs and a matrix of demineralized bone tissue which can be formulated into sponge-like material as made obvious by the combination of Thorne, Urist and McKay, McKay further teaches that bone-derived tissue may be combined with a solvent to form a material (Col. 19, lines 46-47) prior to being extruded (Col. 19, lines 30 and 62), cast, molded (Col. 19, lines 54 and 62), into a structural shape. McKay teaches that the solvent can be “lower alkanols”, which is considered to reasonably read on ethanol (Col. 19, lines 46-48). Thus, one having ordinary skill in the art would recognize based on the additional teachings of McKay that mixing the osteoinductive composition with ethanol prior to shaping could be used to produce the osteoinductive composition formed as a sponge-like material.
McKay is silent as to the specific ratio of solvent to demineralized bone tissue comprising BMPs used in order to produce the osteoinductive implant. However, the desired or workable ratios of solvent to demineralized bone tissue comprising BMPs could be readily derived by one having ordinary skill in the art via routine optimization. A skilled artisan would recognize that adjustments in the ratio of liquid solvent to demineralized bone tissue comprising BMPs would result in osteoinductive compositions possessing different structural qualities ranging from more liquid to more solid forms and which could be adjusted based on the desired type or structural qualities of osteoinductive implant or the location at which the osteoinductive implant was intended to be used. Thus, it would be within the ambit of a skilled artisan to arrive at a ratio of 2-4:1 ethanol to bone composition by weight as instantly claimed via routine optimization. See MPEP 2144.05(II)(A) as recited above.
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 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 demineralized bone tissue and BMPs 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 demineralized bone tissue and BMPs can be sterilized with radiation.
Urist teaches wherein 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]) and 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 which and BMPs 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.
Declaration under 37 CFR 1.132
The declaration under 37 CFR 1.132 filed Dr. William Walsh on January 26, 2026 has been considered and is insufficient to overcome the rejection of the instant claims based upon 35 U.S.C. 103 as set forth in the last Office action for the reasons set forth below:
Response to Arguments
Applicant's arguments and Dr. Walsh’s declaration filed January 26, 2026 are acknowledged and have been fully considered but they are not persuasive.
Applicant traverses on Pg. 11 (last para.) that the combination of Thorne, Urist, McKay, and Lee fails to teach or suggest every limitation of the instant claims and on Pg. 12 (first para.) that the office has not articulated a reason which a skilled artisan would combine the known elements to achieve the claimed invention. Applicant asserts on Pg. 12 (2nd para.) and Dr. Walsh declares in point 3 that the present claims are drawn to a method of producing an osteoinductive composition by obtaining bone tissue, cleaning the bone tissue via washing, demineralizing the bone tissue via soaking an acid solution comprising a salt at 0.5M to 10M concentration, sterilizing the bone tissue with radiation, and yielding an osteoinductive composition having a bone protein concentration comparatively greater than bone tissue soaked in acid without a salt. Applicant further asserts (Pg. 12, 3rd para.) and Dr. Walsh declares (Pt. 3) that the goal of the present method is to demineralize the bone tissue to remove the mineral component and leave behind collagen and growth factors (e.g., BMPs) on the bone tissue and subsequently use the demineralized bone tissue for implantation. Applicant traverses and Dr. Walsh declares (Pt. 6) that the prior art of Thorne and Urist teach extraction and isolation of BMPs which differs from the instant method where BMPs remain attached to the demineralized bone tissue as the addition of the salt to the acid demineralization solution changes diffusion kinetics and charge/structure of the bone proteins.
First, Applicant traverses on Pgs. 13-14 and Dr. Walsh declares in Pts. 7-12 that Thorne and Urist are not analogous art as they are not drawn to retention of the native bone proteins on the demineralized bone tissue as intended by the instant invention, but instead are drawn to extraction of BMPs from bone tissue. Applicant asserts on Pg. 14 (1st full para.) that Thorne and Urist are directed to a different problem than the instant invention and one of ordinary skill would not have sought the teachings of Thorne and Urist to solve the problem of the instant invention.
Applicant’s assertion of non-analogous art has been fully considered but is not persuasive.
In response to applicant's argument that Thorne and Urist are nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, the prior art of Thorne and Urist is drawn methods of production of osteoinductive compositions comprising demineralization of bone tissue in order to expose native bone proteins (BMPs) and subsequent use of the osteoinductive composition for implantation which is the same field of endeavor of the instant invention. MPEP 2141.01(a)(1) states (emphasis added):
“A reference is analogous art to the claimed invention if: (1) the reference is from the same field of endeavor as the claimed invention (even if it addresses a different problem); or (2) the reference is reasonably pertinent to the problem faced by the inventor (even if it is not in the same field of endeavor as the claimed invention). Note that “same field of endeavor” and “reasonably pertinent” are two separate tests for establishing analogous art; it is not necessary for a reference to fulfill both tests in order to qualify as analogous art. See Bigio, 381 F.3d at 1325, 72 USPQ2d at 1212.”
Second, Applicant asserts on Pg. 14-15 and Dr. Walsh declares in Pg. 13 that application of the teachings of Thorne and Urist would not have resulted in the presently claimed method. Applicant traverses that Urist is antithetical to the claimed method which exposes native bone proteins on the bone tissue as Urist teaches extraction of BMPs from bone tissue rather than retention on the collagen matrix. Applicant traverses that Thorne also teaches solubilization and extraction of BMPs from bone tissue, purification, and isolation of BMPs rather than retention on the collagen matrix. Applicant asserts that a skilled artisan, applying the teachings of Thorne and Urist, would be directed to extract BMPs from bone tissue which would not result in the claimed invention.
Applicant’s assertion related to teachings of the prior art changing the function of the instantly claimed invention have been fully considered but are not persuasive.
The office agrees with Applicant’s assertions that Thorne and Urist are drawn to extraction of BMPs for further processing as an osteoinductive composition and not to methods of increased retention of BMPs on demineralized bone tissue. In other words, in the teachings of Thorne and Urist, the osteoinductive composition is the extract from demineralized bone tissue which comprises BMPs whereas Applicant asserts and Dr. Walsh declares that the instant declaration is drawn toward an osteoinductive composition which is demineralized bone tissue with retained non-solubilized BMPs. However, Applicant’s invention as instantly claimed does not limit the osteoinductive composition to the bone matrix. In fact, Applicant’s instant dependent claim 11 indicates that the osteoinductive composition further comprises collagen and/or demineralized bone matrix. Applicant’s assertion and Dr. Walsh’s declaration appears to indicate that osteoinductive composition of the instantly claimed method would necessarily include demineralized bone matrix in the form of collagen. Thus, a one of ordinary skill would have every reason to believe that the osteoinductive composition as instantly claimed would not comprise demineralized bone matrix/collagen. Therefore, the office concludes that the broadest reasonable interpretation of the instantly claimed osteoinductive composition includes an extract from demineralized bone tissue which comprises BMPs as taught by both Thorne and Urist.
In response to applicant's argument that the references fail to show certain features of applicant’s invention, it is noted that the features upon which applicant relies (i.e., the osteoinductive composition comprises the matrix) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997) (The court held that the PTO is not required, in the course of prosecution, to interpret claims in applications in the same manner as a court would interpret claims in an infringement suit. Rather, the “PTO applies to verbiage of the proposed claims the broadest reasonable meaning of the words in their ordinary usage as they would be understood by one of ordinary skill in the art, taking into account whatever enlightenment by way of definitions or otherwise that may be afforded by the written description contained in applicant’s specification.”). See MPEP 2111.
As such, Dr. Walsh’s declaration provides no showing that the objective evidence of nonobviousness is commensurate in scope with the claims as it pertains to the method of producing an osteoinductive composition as recited in claims 1, 12, and 32. See MPEP § 716.
Third, Applicant asserts on Pg. 15 (last para.) and Dr. Walsh declares in Pts. 14-15 that Thorne, which teaches that addition of calcium chloride can be used to enhance mineral solubility, in fact teaches away from a modification via addition of calcium chloride. Applicant asserts that a skilled artisan would recognize that addition of calcium chloride would slow and limit demineralization and, as such, disregard Thorne’s teaching of addition of calcium chloride to demineralization solution.
Applicant’s assertion of teaching away has been fully considered but is not persuasive.
In response to Applicant's arguments against the reason to combine the prior art references, MPEP 2144 (IV) states that the reason or motivation to modify a reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by Applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006). In instant case, the prior art teaches to …. The fact that Applicant has recognized another advantage 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).
Thorne teaches that the demineralization solution can comprise additives such as calcium chloride and that salts such as calcium chloride can enhance the solubility of the bone materials (Para. [0034]). Thorne’s teaching of improvement of bone material solubility is considered to reasonably include bone proteins. Urist also teaches that calcium chloride can be used to enhance solubility of bone proteins. Therefore, based on the scope of the instantly claimed invention, a skilled artisan would be likely to apply the teachings of Thorne and Urist, where addition of calcium chloride can be used in order to enhance bone protein solubility.
Additionally, it is noted that Applicant’s instant claims 7, 9, and 18 indicate that calcium chloride can used as the salt for the demineralization solution which is an acid containing a salt.
Fourth, Applicant asserts on Pg. 16 and Dr. Walsh declares in Pt. 18 that the addition of salt to the acid-based demineralization solution generates an ionic solution which may exhibit charge shielding of proteins thereby reducing electrostatic interactions, reducing the electrostatic repulsion between proteins which allows proteins to be closer and for more proteins to be retained on the demineralized bone matrix which results in increased osteoinductive potential. It is noted that the effects of salt on proteins in a solution are well known. Chi et al. (2003, Physical Stability of Proteins in Aqueous Solution: Mechanism and Driving Forces in Nonnative Protein Aggregation, Pharma. Res., 20(9), 1325-1336, found in IDS dated 07/29/2022) teaches that salts bind to proteins and can affect conformational stability as well as modulate the strength of electrostatic interactions within and between proteins. Chi et al. further teaches that the effects of salt on proteins is salt and concentration dependent with charge shielding caused by ions in solution reducing electrostatic interactions between proteins occurring at low concentrations and increases in protein solubility occurring at high concentrations. Chi et al. teaches that the effect of a salt on protein stability is a net effect of multiple mechanisms which are dependent upon the salt, pH, and concentration (Pg. 1327, Salt Type and Concentration).
Applicant traverses on Pg. 17 that the instantly claimed invention exhibits the alleged unexpected result of generation of an osteoinductive composition exhibiting increased bone protein concentration and enhanced osteoinductivity and that the claimed method provides alleged advantaged over the prior art of the method of Thorne and Urist would could not have been predicted. Dr. Walsh declares in the supplemental data detailed in Pts. 20-29 that during studies investigating pairwise comparison between bone tissue demineralized in a 0.5M hydrochloric acid (HCl) solution comprising water (control) and bone tissue demineralized in a 0.5M HCl comprising 1M sodium chloride (NaCl, test), that bone volume, bone formation, and amount of BMP-2 (as measured by ELISA) were greater in bone tissue demineralized with HCl comprising 1M NaCl (See table, Pt. 20). Dr. Walsh declares that investigation of bone fibers demineralized under control and test conditions indicated increased BMP-2 (See graph Pt. 21) and increased bone formation (See graphs Pts. 22 and 22) in bone fibers demineralized with HCl comprising 1M NaCl. Dr. Walsh declares that bone tissue demineralized with HCl comprising 1M NaCl increased the osteoinductivity of the demineralized bone tissue when compared to control demineralized bone tissue as demonstrated by increased bone formation (images Pts. 25-27) and increased bone volume (Pt. 27). Dr. Walsh declares in Pt. 28 that bone samples demineralized with HCl comprising 1M NaCl exhibit increased alkaline phosphatase staining (left image) compared to control (right image) which indicates increased osteoinductivity following demineralization with HCl comprising 1M NaCl.
Applicant’s traversal regarding unexpected results have been fully considered but is not persuasive.
As detailed above, Applicant’s invention as instantly claimed is considered to encompass osteoinductive compositions which are comprised of BMPs extracted from demineralized bone tissue and subsequently used as an osteoinductive implant. Thorne teaches that extracted BMPs can be recombined with demineralized bone matrix for use as an implant. The prior art of Thorne and Urist teach that addition of salt to acid-based demineralization solution would improve protein solubility, thereby generating an extract from demineralized bone tissue which would have a greater number of BMPs that extracts from bone tissue demineralized without a salt. A skilled artisan would reasonably expect that an osteoinductive composition having an increased number of BMPs would exhibit increased osteoinductivity. Thus, it appears that the claimed invention exhibits results that would be expected based on the teachings of the prior art.
Accordingly, Dr. Walsh’s declaration includes statements which amount to an affirmation that the claimed subject matter functions as it was intended to function. This is not relevant to the issue of nonobviousness of the claimed subject matter and provides no objective evidence thereof. See MPEP § 716.
Further, the scope of the independent claims encompass any salt (as per claims 1 and 12), combined with any acid (as per claims 1 and 12), and encompass over an order of magnitude of salt concentrations (as per claims 1 and 12) which can be used to expose any bone protein (as per claims 1, 12, and 32). 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). 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
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIN V PAULUS whose telephone number is (571)272-6301. The examiner can normally be reached Mon-Fri 8 AM-5 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Doug Schultz can be reached at 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631