DETAILED ACTION
Claims 28-45 are currently pending in the application and under examination as presented in the claims filed 01 March 2024. Claims 28, 41 and 43 are independent claims.
An action on the merits follows. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/BR2022/050348, filed 01 September 2022, which claims priority to BRAZIL 1020210174650, filed 02 September 2021. Filing of a certified untranslated copy of the BRAZIL 1020210174650, filed 02 September 2021, is acknowledged.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Thus, the earliest possible priority for the instant application is 02 September 2021.
Information Disclosure Statement
The information disclosure statements filed 16 May 2024 have been considered by the Examiner.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 28-45 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. Claims 29-42 and 44-45 are included in this rejection due to their dependence on and/or encompassing of independent claim 28.
Independent claim 28 recites “in a 50% ethanol solution and indomethacin”, which is indefinite because it is unclear whether the indomethacin is meant to be part of/ dissolved in the 50% ethanol solution in which the collagenous connective tissue is present or whether the indomethacin is distinct from the 50% ethanol solution. If the latter, it is unclear what the relationship is between the indomethacin and the collagenous connective tissue stored for transport in a 50% ethanol solution. As such, the metes and bounds of the claim cannot be determined.
Claim 43 recites “A kit for producing preserved collagenous connective tissue, wherein the kit comprises the collagenous connective tissue of claim 41" in lines 1-2, which is indefinite because claim 41 is a collagenous connective tissue preserved according to the method of claim 28. As such, it is unclear how the kit of claim 43 is “for producing preserved collagenous connective tissue” but comprises collagenous connective tissue which has already been preserved. Additionally, the specification only teaches “KIT FOR IMPLANT IN TISSUES” [title] and “a surgical kit comprising the preserved collagen connective tissue and stabilized” [0069] without reciting any kit for producing preserved collagenous connective tissue. As such, the metes and bounds of the claim cannot be determined.
Claim Interpretation
Claims 30, 35, 38, and 43 recite concentration percents “by volume”, which has been interpreted to encompass a weight to volume percentage in grams (g) per 100 milliliters (mL).
Claim 40 recites, “wherein step c), step d), and step f) are carried out in an immersion time of 24 to 96 hours” in lines 1-2, which has been interpreted to encompass alternatively individual immersion times for each step or a total immersion time for all three steps combined.
Claim 41 recites ”A collagenous connective tissue preserved according to the method of claim 28”. Note that the method of claim 28 requires active method steps; such as stabilizing the collagenous connective tissue with a 50% ethanol solution, treating the collagenous connective tissue with a solution of polyethylene glycol, sterilizing the collagenous connective tissue with a 50% ethanol solution and a 1.5% hydrogen peroxide solution, and incubating/storing the collagenous connective tissue for transport in a 50% ethanol solution and indomethacin; which alter the structure of the collagenous connective tissue such that it is structurally distinct from a naturally occurring collagenous connective tissue.
For example, Cheung teaches that the process permits the residual antigenic components to be masked by PEG, the tissue to be oxidized to reduce recruitment of inflammatory cells, and the tissue to incorporate water insoluble anti-inflammatory agents that inhibit the arrival of inflammatory cells at the implant site [US20040057936A1, 0029]. Therefore, the process alters the structure from the collagenous connective tissue originally removed from the animal donor at least by incorporating PEG, oxidizing the tissue, and incorporating the anti-inflammatory agent indomethacin. As such, no 101 product of nature rejection is being applied to claims 41 and 44-45.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 28-45 are rejected under 35 U.S.C. 103 as being unpatentable over Cheung [US20040057936A1]; in view of Liu [CN104055795A, published 24 September 2014]; Ince & Groeneveld [2014, Kidney International, 86, 1087-1095]; Mohan [2006, Calbiochem Buffers: A guide for the preparation and use of buffers in biological systems, EMD, 1-38]; Edwards Lifesciences [2017, Duravess Bovine Pericardial Vascular Patch Instructions for Use, 1-3]; Mendoza-Novelo & Cauich-Rodriguez [2009, Journal of Applied Biomaterials & Biomechanics, 7(2), 123-131]; Armstrong et al. [2019, Experimental Eye Research, 182, 65-73]; and McFetridge et al. [2004, Journal of Biomedical Materials Research Part A, 70A(2), 159-360].
Regarding independent claim 28, note that the method steps as recited do not require that they be performed in any particular order.
Cheung teaches a method of producing preserved collagenous connective tissue from an animal donor source comprising the steps of:
removing collagenous connective tissue from an animal donor source and trimming the collagenous connective tissue removed from the animal donor source in a saline solution [Figure 1];
rinsing the tissues in saline before using them for studies [0054];
stabilizing the collagenous connective tissue with a 50% ethanol solution [0044, Figure 1];
treating the collagenous connective tissue with a solution of polyethylene glycol [0045, Figure 1];
washing and conserving the collagenous connective tissue in a 50% ethanol solution [0032, 0048, Figure 1];
sterilizing the collagenous connective tissue with hydrogen peroxide [0054, 0074];
treating tissue with a solution of indomethacin in 50% ethanol and thereafter storing or sending for storage [abstract, 0033, 0049-0050, Figure 1].
Cheung does not explicitly state wherein the saline solution in steps a) and b) is a buffer solution. However, Cheung states that the tissue is kept from being degraded by placing the tissue in a physiological saline solution at low temperature, such that blood and other soluble substances are rinsed away using large volumes of cold saline and the excess tissue is trimmed away, wherein collagen matrix in physiological saline with the proper pH and low temperature is stable and proteolytic activities resulting from cell death can also be minimized under such conditions [0043]. Additionally, Cheung teaches wherein “saline” used in later steps of the procedures was formulated as saline in PBS [0068-0069]. Therefore, an ordinarily skilled artisan would have been motivated to use a buffered saline solution, such as a phosphate buffered saline solution, in the removing and washing steps of a) and b) to ensure a proper pH to stabilize the collagen matrix and minimize proteolytic activities.
As discussed above, Cheung teaches sterilizing the collagenous connective tissue with hydrogen peroxide [0054, 0074]. Cheung additionally teaches subjecting the collagenous connective tissue to a 50% ethanol solution and to a 0.1% to 2% hydrogen peroxide (H2O2) solution (e.g., specific use of 0.5% H2O2 in the examples) [0031, 0044, 0046, Figure 1]. Cheung further teaches that concentrations of hydrogen peroxide in excess of 2% are to be avoided to prevent excessive oxidation [0046].
However, Cheung does not explicitly teach that the 50% ethanol solution and a 1.5% hydrogen peroxide (H2O2) solution sterilize the collagenous connective tissue as required in step f).
Liu teaches sterilization treatments of collagenous tissue (e.g., amnion) comprising using a 1% to 3% hydrogen peroxide solution and a 60 to 90% ethanol solution, with specific embodiments using 1%, 2%, or 3% hydrogen peroxide solutions paired with 60, 75, or 90% ethanol solutions [0035, 0078, 0085, 0093, 0101]. Therefore, Liu teaches wherein treatment of a collagenous connective tissue with 1-3% H2O2 and with 60% ethanol has a sterilizing effect [0035, 0078, 0085, 0093, 0101]. Liu also teaches that the combination of 3% H2O2 with 90% ethanol, 1% H2O2 with 60% or 75% ethanol, as well as 2% H2O2 with 75% ethanol resulted in prepared amnion implant with stable quality which retained the natural collagen in the amniotic membrane and/or exhibited a good repairing effect on deep lip nose groove wrinkles or canthus fine lines [0083, 0090-0091, 0098-0099, 0106-0107]. As such, given the teachings of Liu of sterilization of collagenous connective tissue using a 60% ethanol solution and a 1% H2O2 solution [0093], an ordinarily skilled artisan would expect the 50% ethanol solution and a 1.5% hydrogen peroxide (H2O2) solution to sterilize the collagenous connective tissue.
Further, given the teachings of Cheung to use 0.1-2% hydrogen peroxide and that concentrations over 2% are to be avoided to prevent excessive oxidation; and the teaching of Liu to use 1-3% H2O2 , wherein each of 1%, 2%, and 3% H2O2 were used to sterilize a collagenous connective tissue to generate amnionic membrane extracellular matrix which was successfully implanted into a patient and produced desirable results; an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use H2O2 at a concentration of 1-2% to sterilize the tissue, prevent excessive oxidation, and achieve desirable results upon implantation of the tissue, and as such, it would have been obvious to an ordinarily skilled artisan to select a concentration of 1.5%.
Also note that, 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 reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05. Both Cheung and Liu teach to use a concentration of hydrogen peroxide in a relatively small range which encompass the claimed 1.5%. Therefore, it would have been obvious to an ordinarily skilled artisan to use any concentration within the ranges taught by Cheung and Liu, and recitation of a specific concentration within that narrow range will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical.
Cheung does not explicitly teach storing the collagenous connective tissue for transport in a 50% ethanol solution and indomethacin (claim 28, step g)) .
However, Cheung teaches to treat the tissue as indicated in schematic 6 and then send to storage [0049, Figure 9] without any requirements to change the solution in which the tissue is submerged. Further, “sent to storage” indicates a transportation of the tissue. As such, the teachings of Cheung encompass and suggest storing the collagenous connective tissue for transport in the solution of indomethacin in 50% ethanol.
Additionally, “for transport” represents an intended use of the stored collagenous connective tissue and not an active step of the method. As such, the storing step merely needs to produce a collagenous connective tissue in a 50% ethanol and indomethacin solution capable of being transported. Applicant is reminded that a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure (i.e., a collagenous connective tissue in a 50% ethanol and indomethacin solution) is capable of performing the intended use (i.e., being transported), then it meets the claim. It is a general rule that merely discovering and claiming a new benefit to an old process cannot render the process again patentable. In re Woodruff, 919 F. 2d 1575, 1577-78, 16 USPQ2d 1934, 1936-37 (Fed.Cir. 1990); In re Swinehart, 439 F.2d 210, 213, 169 USPQ 226, 229 (CCPA 1971); and Ex Parte Novitski, 26 USPQ2d 1389, 1391 (Bd. Pat. App. & Int. 1993). In the instant case, Cheung teaches sending a collagenous connective tissue in a 50% ethanol and indomethacin solution for storage, which therefore meets the structural limitations of step g) to produce a stored product which is capable of being transported.
Given the motivation taught by Cheung to use a buffered saline solution, such as a phosphate buffered saline solution, in the removing and washing steps of a) and b) to ensure a proper pH to stabilize the collagen matrix and minimize proteolytic activities; and the motivation taught by Cheung and Liu to use H2O2 at a concentration of 1-2% to prevent excessive oxidation and to achieve desirable results upon implantation of the tissue; it would have been prima facie obvious to an ordinarily skilled artisan to modify the method of Cheung to use a buffered saline solution for steps a) and b) and to select a concentration of 1.5% H2O2 for the sterilization of step f) with a reasonable expectation of success.
Regarding claims 29-32, Cheung and Liu teach all the limitations of independent claim 28. As discussed above, Cheung teaches to use physiological saline at an appropriate pH [0043]. Cheung also teaches the use of phosphate-buffered saline [0068-0069]. Cheung also teaches wherein the physiological saline with the proper pH is at a temperature ranging from 4-10 oC, which is within the temperature range of 5-15 oC recited in instant claim 31 [0043].
Cheung does not teach wherein the buffer solution of step a) comprises a solution of phosphate buffer and 0.9% sodium chloride (NaCl) nor wherein the solution of phosphate buffer comprises a mixture of 0.1% monobasic sodium phosphate (NaH2PO4) by volume and 0.6% dibasic sodium phosphate (Na2HPO4) by volume. Note that % by volume has been interpreted to encompass weight per volume concentrations, such as grams (g) per milliliter (mL) wherein 1% is 1 g solute in 100 mL solution.
Ince teaches physiological saline comprises 0.9% NaCl [column 2 ¶ 1]. Therefore, Cheung teaches to use a saline solution which comprises 0.9% NaCl.
Mohan teaches that phosphate and bicarbonate buffer systems are most predominant in biological systems, and that the phosphate buffer system provides effective buffering in the pH range of 6.4 to 7.4 [page 10 ¶ 3-4]. Mohan further teaches the pH of various extracellular fluids, including plasma with a pH range of 7.35-7.45, cerebrospinal fluid with a pH of 7.4, saliva with a pH range of 6.4-7.4, tears with a pH range of 7.0-7.4, aqueous humor with a pH of 7.4, pancreatic juice with a pH range of 7.0-8.0, and sweat with a pH range of 4.5-7.5 [page 27 lower table]. Therefore, given the teachings of Mohan of the suitability of phosphate buffering systems for biological applications, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use a phosphate buffer for applications involving a biological tissue sample and to use a physiological pH in the range of 7.35-7.45 corresponding to the pH of plasma (and multiple other extracellular fluids) to maintain the physiological suitability of the buffer for a biological sample.
Mohan also teaches that mixing both monobasic and dibasic sodium phosphates is a long-established method of choice for preparing phosphate buffer, wherein mixing appropriate amounts of monobasic and dibasic sodium phosphate solutions allows preparation of buffers in the desired pH range [page 17 ¶ 1]. Mohan also teaches to prepare a phosphate buffer solution of pH 7.4 by preparing 0.1 M stock solutions of each of the monobasic and dibasic sodium phosphate and subsequently combining aliquots of each of the 0.1M monobasic and dibasic sodium phosphate stock solutions to produce a final phosphate buffer solution [page 20 ¶ 3-4, second table].
The protocol taught by Mohan teaches to add 13.8 g/L of sodium phosphate monobasic monohydrate (MW of 138.0 g/mol) to prepare the 0.1 M stock solution, and to use 19.0 mL of the 0.1 M stock solution of sodium phosphate monobasic monohydrate in the final phosphate buffer solution pH 7.4. As such, the % sodium phosphate monobasic monohydrate in the final phosphate buffer solution is: 13.8 g / 1000 mLstock * 19.0 mLstock / 200 mLfinal = 0.1% weight/volume (w/v).
The protocol taught by Mohan teaches to add 26.8 g/L of sodium phosphate dibasic heptahydrate (MW of 268.0 g/mol) to prepare the 0.1 M stock solution, and to use 81.0 mL of the 0.1 M stock solution of sodium phosphate dibasic heptahydrate in the final phosphate buffer solution pH 7.4. As such, the % sodium phosphate dibasic heptahydrate in the final phosphate buffer solution is: 26.8 g / 1000 mLstock * 81.0 mLstock / 200 mLfinal = 1.1% w/v. However, substitution of sodium phosphate dibasic monohydrate for the sodium phosphate dibasic heptahydrate, which has 6 fewer water molecules and as such has a molecular weight of 268-(6*18)=160 g/mol, would produce the same molar concentration of phosphate in each of the stock and final solutions, but with a % w/v as follows: 16.0 g / 1000 mLstock * 81.0 mLstock / 200 mLfinal = 0.6% w/v.
Therefore, Mahon teaches to prepare a phosphate buffer solution which comprises a mixture of 0.1% monobasic sodium phosphate (monohydrate) by volume and 0.6% dibasic sodium phosphate (monohydrate) by volume as a suitable buffer with a physiological pH for use with biological samples.
Mahon also teaches the addition of NaCl to buffers, including a phosphate buffer, at a final concentration of 150 mM, which corresponds to 8.7 g NaCl / L, which in turn corresponds to 0.9% NaCl in the solution [page 22 ¶ 5, page 23 ¶ 1].
Regarding claim 33, Cheung and Liu teach all the limitations of independent claim 28. Cheung teaches wherein the collagenous connective tissue is pericardium [0002-0003, 0005, 0074-0076]. Cheung also teaches rinsing the collagenous connective tissue with large volumes of cold saline, but does not teach a specific volume for washing the collagenous connective tissue of step b).
Edwards teaches that adequate rinsing with sterile physiological saline according to their instructions is mandatory before implantation of bovine pericardial vascular patches to reduce the glutaraldehyde concentration [column 1 ¶ 5]. Edwards further teaches that the rinsing is performed on a piece of pericardium at least twice with 500 ml of sterile physiological saline such that the fluid level is sufficient to completely submerge the tissue [column 1 ¶ 1, column 3 ¶ 5-8]. Therefore, in preparing a pericardium for transplantation, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to rinse a pericardium in 500 mL of a rinse solution to ensure that the pericardium can be completely submerged within the fluid and to reduce the concentration of potentially interfering substances, such as glutaraldehyde.
Regarding claim 34, Cheung teaches wherein the stabilization is performed at a temperature of 4 to 10 oC [abstract].
Regarding claims 35-36, Cheung teaches that the concentration of PEG in the solution of step d) may vary between 1% and 15%; the concentration of hydrogen peroxide in the range of 0.1 to 2% may be used; the salt is preferably sodium chloride with a concentration between 2.5 and 4.5M; and the phosphate buffer is selected from sodium phosphate and potassium phosphate, with concentrations between 0.02 to 0.1M and pH of 6.5-7.8 [0046-0047]. Cheung teaches wherein the PEG solution of step d) preferably comprises a mixture of 5% PEG, 4M NaCl, 0.05M phosphate buffer at pH 7.4, and 0.5-0.6% H2O2 incubated at a preferable temperature of 4 oC for 96 hours [0045].
Note that the range of 2.5M to 4.5M NaCl taught by Cheung corresponds to 14.6% to 26.3% w/v of NaCl; the instantly claimed 32% NaCl in w/v corresponds to 5.5M. Further, Cheung teaches that collagen molecules and fibers in animal tissue are very stable in salt concentrations above 3 Normal at neutral pH, such that high salt concentration are used to stabilize the tissue while the oxidation reaction is carried out [0039]. Cheung further teaches that soaking tissue in high salt concentrations removes certain non-collagenous material while keeping the tissue intact [0041]. As such, an ordinarily skilled artisan would have been motivated to select a NaCl concentration above 3M for the solution of PEG of step d) to remove certain non-collagenous material while keeping the tissue intact. Accordingly, the instantly claimed concentration of 32% NaCl is “above 3 Normal”, which Cheung teaches stabilizes the tissue while the oxidation reaction in a solution comprising PEG and H2O2 is carried out. As such, the recited 32% NaCl falls within the range (i.e., above 3 Normal) taught by Cheung.
Note also that the range of 0.02M to 0.1M sodium phosphate buffer taught by Cheung corresponds to 1.4% w/v of anhydrous dibasic sodium phosphate; the instantly claimed 13% in w/v corresponds to approximately 0.9M for anhydrous dibasic sodium phosphate or approximately 1.3M for the phosphate ions themselves. None of Cheung, Liu, Ince, Mohan, nor Edwards specifically teach to incubate the collagenous connective tissue in a PEG solution comprising 13%/1M phosphate buffer.
As discussed above, note that, 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. Therefore, recitation of a concentration (i.e., 13% phosphate buffer) which falls outside of the range taught by Cheung will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical.
Further, Mendoza-Novelo teaches the use of 1.0 M phosphate buffer for incubating decellularized collagenous connective tissue (i.e., bovine pericardium) [page 125 column 1 ¶ 3], thereby teaching that 1.0 M phosphate buffer is a suitable buffer for incubating a decellularized collagenous connective tissue.
Regarding claim 37, Cheung and Liu teach all the limitations of independent claim 28. Cheung teaches wherein the 50% ethanol solution of step e) is at a temperature of 4 to 25 oC [0048, claim 8, 49]. Therefore, it would have been obvious to an ordinarily skilled artisan to select any temperature within the recited range, including a temperature of about 25 oC.
Regarding claim 38, Cheung and Liu teach all the limitations of independent claim 28. Cheung teaches using indomethacin in the solution of step g) at a concentration of 20 mg/L or 50 mg/L, wherein the concentration may be in the range of 10 mg to 200 mg per liter, which corresponds to 0.001% to 0.02% indomethacin by w/v [0049, 0051, 0054]. Cheung also teaches that the amount of indomethacin should be in the range used for humans on a dose/kg body weight basis, such that high dosages of the anti-inflammatory agent are to be avoided because the tissue can be damaged and become toxic to host cells [0049]. Cheung also teaches wherein the concentration of the anti-inflammatory agent is in the range of 10 to 200 mg/liter [0033].
Armstrong teaches that indomethacin at 0.03, 0.1, and 0.3% wt/vol concentrations were chosen for their studies to mirror doses in clinically available topical preparations [page 67 column 1 ¶ 3]. Armstrong also teaches that indomethacin alone was able to mitigate human Tenon’s capsule fibroblast (HTCF)-mediated changes in collagen remodeling, and that the combined anti-contractile and anti-remodeling effects of indomethacin suggest a capacity to mitigate many of the histopathological findings associated with failed filtration blebs [page 70 column 1 ¶ 2, page 72 column 1 ¶ 1]. Armstrong also teaches that NSAIDS, including indomethacin, are effective at mitigating wound healing during the post-operative phase [page 71 column 1 ¶ 1].
Therefore, given the teachings of Cheung to use an amount of indomethacin in the range used for humans, the teachings of Armstrong that indomethacin at 0.03, 0.1, and 0.3% wt/vol concentrations mirror doses in clinically available preparations, and teachings of Armstrong that such doses of indomethacin have a capacity to mitigate wound healing, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use an indomethacin concentration in the range of 0.03-0.3% to align with clinically available preparations for the treatment of collagenous connective tissue to aid in mitigating wound healing following surgical implantation of the prepared tissue.
Additionally, as discussed above, differences in concentration, temperature, or time will not generally support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration, temperature, or time is critical. See MPEP 2144.05. Cheung teaches to use a range of indomethacin concentrations which correspond to 0.001% to 0.02% wt/vol and Armstrong teaches to use a range of indomethacin concentrations of 0.03% to 0.3% wt/vol. Therefore, the ranges taught by Cheung and Armstrong encompass the recited concentration of 0.05% indomethacin. As such, it would have been obvious to an ordinarily skilled artisan at the time of filing to select any concentration within the range taught by Cheung and Armstrong, and recitation of a specific concentration within that range will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical.
Regarding claim 39, Cheung and Liu teach all the limitations of independent claim 28.
With respect to the washing step b), Cheung teaches rinsing away the blood and other soluble substances using large volumes (plural) of cold saline [0043]. By using the plural term “volumes”, Cheung teaches to perform multiple rinse/wash steps.
Liu teaches a washing step of the amnion in PBS followed by 1-5 water washes to clean the isolated amnion [0035], with multiple specific washes at 1x, 2x, 3x, or 5x [0064, 0071, 0078, 0085, 0093, 0101]. Therefore, Liu teaches to wash the tissue 2-6x to clean the tissue prior further processing, including sterilization and decellularization.
Given the teachings of Liu to perform 2-6 wash steps to clean the collagenous connective tissue prior to decellularization, an ordinarily skilled artisan at the time of filing would have been motivated to perform the washing step multiple times as taught by Cheung to rinse away the blood and other soluble substances, and in so doing would be motivated to use a number of washing steps as taught by Liu for cleaning a collagenous connective tissue, including any number of washes from 2 to 6 times.
With respect to the stabilizing step c), none of Cheung, Liu, Ince, Mohan, Edwards, Mendoza-Novelo, nor Armstrong teach to repeat the stabilization step c).
However, McFetridge teaches processing of collagenous connective tissue (i.e., carotid arteries) comprising trimming of excess connective tissue followed by treatment with 75% ethanol for 72 hours, wherein the solvent replacement was performed at 1, 3, 6, 12, 24, and 72 hours [page 225 column 2 ¶ 4]. McFetridge additionally teaches that the 75% ethanol treatment resulted in extracting all detectable triglyceride at 12 hours [page 227 column 2 ¶ 1]. McFetridge also teaches that the single treatment of 75% ethanol (i.e., ethanol treatment without another organic solvent) was selected as the solvent of choice because of minimal material handling, excellent solubility, and indirect effects such as minimizing tissue calcification [page 230 column 2 ¶ 2]. McFetridge further teaches that ethanol pretreatments have been shown to stabilize collagen-based biomaterials against enzymatic digestion, reduce the total water content, and minimize calcification [page 230 column 2 ¶ 2]. Therefore, given the teachings of McFetridge that pre-treatment with ethanol, wherein the ethanol solution is changed out 6 times over the course of 72 hours, results in complete extraction of triglycerides, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to repeat the ethanol stabilization step up to 6 times to extract triglycerides in a method for producing preserved collagenous connective tissue.
With respect to the washing step e), Cheung teaches washing the collagenous connective tissue in 50% ethanol twice [0054, 0074, 0077, 0080]. Cheung also teaches that the salt in the tissue is washed away by 50% ethanol preferably until a negligible amount of salt is left in the tissue [0048].
Liu teaches washing steps following decellularization performed 3-10x, with multiple specific washes at 3x, 6x, 7x, or 10x [0041, 0067, 0074, 0081, 0088, 0096, 0104].
Edwards teaches that adequate rinsing of the bovine pericardial vascular patch with sterile physiological saline is mandatory before implantation to reduce the glutaraldehyde concentration and that the rinsing is to be repeated a minimum of one additional time [column 1 ¶ 5, column 3 ¶ 5-8]. Therefore, Edwards teaches washing the tissue two or more times following decellularization.
Given the teachings of Cheung to wash until a negligible amount of salt is left in the tissue; the teachings of Liu to perform 3-10 wash steps to clean the collagenous connective tissue following decellularization; and the teachings of Edwards to wash at least twice; an ordinarily skilled artisan at the time of filing would have been motivated to perform the washing step multiple times as taught by Cheung to rinse until a negligible amount of salt is left in the tissue, and in so doing would be motivated to use a number of washing steps as taught by Liu for cleaning a collagenous connective tissue, including any number of washes from 3 to 10 times, such as the specifically recited 3 washes.
Regarding claim 40, Cheung and Liu teach all the limitations of independent claim 28.
With respect to the immersion time of step c), Cheung teaches wherein the soaking/immersion time for step c) stabilizing the collagenous connective tissue with a 50% ethanol solution is preferably less than 30 days [0031, 0044], which encompasses the recited range of 24-96 hours. Cheung also teaches specifically soaking in the 50% ethanol solution for one week [0054, 0074, 0077].
As discussed above, also note that, generally, differences in concentration, temperature, or time will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration, temperature, or time is critical. See MPEP 2144.05. Cheung teaches to use a soaking time for stabilization in 50% ethanol within a relatively small range which encompasses the claimed 24-96 hours. Therefore, it would have been obvious to an ordinarily skilled artisan at the time of filing to select any time within the range taught by Cheung, including times which are within the lower portion of the range such as 1-4 days, and recitation of a specific time within that range will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical.
With respect to the immersion time of step d), Cheung also teaches wherein the soaking/immersion time for step d) treating the collagenous connective tissue with a solution of polyethylene glycol is for a period of 96 hours, and that the tissue may alternatively be soaked for periods in the range of 12 hours to 14 days [0045].
With respect to the immersion time of step f), Cheung teaches the inclusion of hydrogen peroxide in the solution used for step d) treating the collagenous connective tissue with a solution of polyethylene glycol, wherein the soaking time is for a period in the range of 12 hours to 14 days and preferably 96 hours. Therefore, Cheung teaches to soak the tissue in a solution comprising H2O2 preferably for 96 hours.
Cheung also teaches soaking the collagenous connective tissue in 50% ethanol at the end of the washing step e) for overnight to as long as 30 days followed by soaking in another 50% ethanol solution preferably for 24 hours [0033, 0048, 0051, 0054].
Additionally, Liu teaches a combined contact time with the ethanol solution and H2O2 solution to sterilize the collagenous connective tissue of 5 minutes to 2 hours [0035, 0093]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would expect that the ethanol solution and H2O2 solution contact times taught by Cheung would be sufficient times for sterilization of the collagenous connective tissue.
Regarding claim 41, Cheung and Liu teach all the limitations of independent claim 28. Additionally, Cheung teach a collagenous connective tissue preserved according to the method for producing preserved collagenous connective tissue from an animal donor source as discussed above [0055-0073, Table 1].
Regarding claim 42, Cheung teaches wherein the collagenous connective tissue comprises a xeno/heterogenous graft, including porcine heart valve leaflets treated and implanted into juvenile sheep [0003, 0080].
Regarding claim 43, the preamble of this claim recites a “kit.” The specification, however, does not define this term, and so it is being interpreted to encompass any collection of reagents that includes all of the elements of the claim. Any further interpretation of the word is considered an intended use and does not impart any further structural limitation of on the claimed subject matter. As discussed above, Cheung and Liu teach the collagenous connective tissue as recited in claim 41 as well as storing the collagenous connective tissue in a solution comprising a mixture of 50% ethanol solution by volume and indomethacin. Additionally, as also discussed above, Armstrong teaches to use a concentration of indomethacin in the range of 0.03% - 0.3%, which mirrors doses in clinically available topical preparations [page 67 column 1 ¶ 3]. Therefore, Cheung, Liu, and Armstrong teach the limitations of claim 43.
Regarding claims 44-45, Cheung teaches generally that the method processes collagenous connective tissue taken from an animal donor for implant into a recipient without restricting the implantation site [0024, 0030, 0036]. Cheung teaches that the collagenous connective tissue may be heart valve tissue, blood vessel, pericardium, omentum, fascia, tendon, ligament, intestine, cartilage, bone, membrane, or other such tissue [0002]. Cheung also teaches that implant materials intended for permanent or long lasting implantation may provide structural support for a body part or may be an active functional organ such as a kidney, liver, or heart [0004]. Cheung further teaches cardiovascular applications as well as non-cardiovascular applications including orthopedics, neurological, and urological applications and also teaches use for tendons and ligaments, conduits for nerve guides, tissue membranes such as tissue patches, urological conduits, etc. [0033-0035, 0049]. Specific examples recite implanting treated porcine mammary arteries into sheep as descending aorta to circumflex artery bypass [Example 3, 0078] and implanting porcine hearth valve leaflets implanted as mitral heart valves replacement in juvenile sheet [Example 4, 0080]. Cheung also teaches wherein the invention relates to a process for treating collagenous connective tissue from an animal donor for implant in an animal or human recipient [0001] and wherein implants from animal donors into a human recipient are for correcting defective body components [0003]. Therefore, Cheung teaches wherein the collagenous connective tissue is used at least in human body applications including heart surgery, neurological surgery, and surgery for correcting parts of the human body.
Cheung does not explicitly recite wherein the collagenous connective tissue is used in any region or organ of the human body. However, the broad language recited by Cheung, as discussed above, encompasses any region or organ of the human body. Additionally, “is used in any region or organ of the human body” is reciting an intended use of the claimed collagenous connective tissue product. As discussed above, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure (i.e., a collagenous connective tissue produced by the method of Cheung and Liu) is capable of performing the intended use (i.e., use in any region or organ of the human body), then it meets the claim. In the instant case, Cheung teaches using a large variety of organs or tissues in the method and using them for repairing a large variety of organs or tissues without reciting any limitations to the regions or organs of the human body which can be targeted. Therefore, the collagenous connective tissue produced by the method taught Cheung and Liu, which teach all the limitations of independent claim 28, is made by the same method as the instantly claimed collagenous connective tissue, and so comprises the same structure as the instantly claimed collagenous connective tissue, and as such is capable of the same uses as the instantly claimed collagenous connective tissue, absent evidence to the contrary.
Given the motivation taught by Mohan to use a phosphate buffer for applications involving a biological tissue sample and to use a physiological pH in the range of 7.35-7.45 corresponding to the pH of plasma (and multiple other extracellular fluids) to maintain the physiological suitability of the buffer for a biological sample; the motivation taught by Edwards to rinse a pericardium in 500 mL of a rinse solution to ensure that the pericardium can be completely submerged within the fluid and to reduce the concentration of potentially interfering substances; the motivation taught by Cheung to select a NaCl concentration above 3M for the solution of PEG of step d) to remove certain non-collagenous material while keeping the tissue intact; the motivation taught by Armstrong to use an indomethacin concentration in the range of 0.03-0.3% to align with clinically available preparations for the treatment of collagenous connective tissue to aid in mitigating wound healing following surgical implantation of the prepared tissue; the motivation taught by Liu and Cheung perform the washing step 2-6 times to rinse away the blood and other soluble substances to clean a collagenous connective tissue; the motivation taught by McFetridge to repeat the ethanol stabilization step up to 6 times to extract triglycerides in a method for producing preserved collagenous connective tissue; the motivation taught by Cheung, Liu, and Edwards to perform the 3 washing steps to rinse until a negligible amount of salt is left in the tissue for cleaning a collagenous connective tissue; it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to modify the method and prepared cartilaginous connective tissue of Cheung to use the phosphate buffer concentrations, pH, wash volumes, NaCl concentration, indomethacin concentration, immersion times, and repeated step counts as recited in the instant claims with a reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 28-45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 19/059,370, filed 01 March 2024, hereafter referred to as the ‘370 application, in view of Harvard T.H. Chan School of Public Health [2021, “Collagen”, The Nutrition Source, retrieved on 16 June 2026 from:<nutritionsource.hsph.harvard.edu/collagen/>, last reviewed May 2021].
The instant claims recite a method for producing preserved collagenous connective tissue from an animal donor source, a collagenous connective tissue preserved by the method of for preserving, and a kit for producing preserved collagenous connective tissue.
The ‘370 application claim 1 recites “A method for producing preserved collagenous connective tissue comprising the following steps:
a) removing collagenous connective tissue from a donor and trimming the collagenous connective tissue in a buffer solution, wherein the buffer solution is a solution of phosphate buffer and 0.9% sodium chloride (NaCI) at a temperature ranging from 5"C to 15*C, and a pH ranging from 7.3 to 7.5;
b) washing the collagenous connective tissue with the buffer solution of step a), wherein the volume of the buffer solution is 500 mL per piece of collagenous connective tissue;
c) stabilizing the collagenous connective tissue with a 50% ethanol solution at a temperature ranging from 2"C to 10"C;
d) treating the collagenous connective tissue with a solution of polyethylene glycol and hydrogen peroxide at a temperature ranging from 2"C to 8"C;
e) washing and conserving the collagenous connective tissue in 50% ethanol solution, wherein the temperature of the 50% ethanol solution is around 25"C;
f) sterilizing the collagenous connective tissue with a 50% ethanol solution and a 1.5% hydrogen peroxide (H202) solution; and
g) storing the collagenous connective tissue for transport in a 50% ethanol solution and indomethacin, wherein the concentration of the indomethacin is about 0.05% by volume.”
The ‘370 application claim 1 therefore recites all the limitations of instant claims 28, 29, 31-38 except that the donor is an animal donor. However, collagen is an animal-specific protein [Harvard page 1 line 1 – page 2 line 4], and as such any donor of a collagenous tissue must be an animal donor. Additionally, the ‘370 application claims 2-9 each recite limitations recited in instant claims 30, 35, and 39-45. Therefore, the ‘370 application claims recite all of the limitations recited in the instant claims. By incorporating some of the dependent limitations of the instant application within the independent claim of the ‘370 application, the ‘370 application represents an obvious species of the instant application. As such, the ‘370 application claims anticipate and render obvious the claims of the instant application.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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