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 .
Claim Status
In the amendment filed 10th, August, 2026, Applicant cancelled claims 11 and 67-68 and added new claim 71.
Claims 1, 4-10, 12-15, 17-21, 25-27, 40, 63-66, and 69-71 are pending.
Claims 7, 25-27, and 69-71 are withdrawn.
Claims 1, 4-7, 9-10, 12-15, 17-21, 40 and 63-66 are under examination.
Election/Restrictions
Note that newly submitted claim 71 is directed to species that are not so linked as to form a general inventive concept under PCT Rule 13.1 for the following reasons:
Newly added claim 71 is dependent on withdrawn claim 69 which is drawn to a method of decellularizing an isolated organ or portion thereof comprising contacting the isolated organ or portion thereof with sodium dodecyl sulfate and a radical generating compound which belongs to the non-elected species of “both a detergent and a radical-generating compound” as originally presented in the Lack of Unity set forth on 6th, September, 2024).
Since applicant has received an action on the merits for the originally presented species, this species has been constructively elected by original presentation for prosecution on the merits.
Accordingly, claim 71 is withdrawn from consideration as being directed to a non-elected species. See 37 CFR 1.142(b) and MPEP § 821.03.
Withdrawn Claim Rejections - 35 USC § 112(a)
Scope of Enablement
The rejection of claims 1, 4-6, 8-10, 12-15, 17-21, 40 and 63-66 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ) first paragraph because the full scope of the claims was not enabled as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Moot Claim Rejections - 35 USC § 112(a)
Scope of Enablement
The rejection of claims 11 and 67-68 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ) first paragraph because the full scope of the claims was not enabled as set forth in the previous office action is moot in view of the cancellation of these claims.
Withdrawn Claim Rejections - 35 USC § 112(b)
The rejection of claims 18 and 21 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Moot Claim Rejections - 35 USC § 112(d)
The rejection of claim 11 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends as set forth in the previous office action is moot in view of the cancellation of this claim.
Moot Claim Rejections - 35 USC § 102
The rejection of claim 67 under 35 U.S.C. 102(a)(1) as being anticipated by Ross (US-2012/0064537-A1; see IDS filed 26th, October, 2021) as set forth in the previous office action is moot in view of the cancellation of this claim.
Moot Claim Rejections - 35 USC § 103
The rejection of claims 11 and 67-68 under 35 U.S.C. 103 as being unpatentable over Ross (US-2012/0064537-A1; see IDS filed 26th, October, 2021) in view of Guyette et al. (Nat Protoc. 2014;9(6):1451-68. Epub 2014 May 29.; henceforth “Guyette”) and Bhaumik et al. (Journal of Membrane Science 235 (2004) 31–41; henceforth “Bhaumik”) as set forth in the previous office action is moot in view of the cancellation of these claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 4-6, 8-10, 12-15, 17-21, 40 and 63-66 remain rejected under 35 U.S.C. 103 as being unpatentable over Ross (US-2012/0064537-A1; see IDS filed 26th, October, 2021) in view of Guyette et al. (Nat Protoc. 2014;9(6):1451-68. Epub 2014 May 29.; henceforth “Guyette”) and Bhaumik et al. (Journal of Membrane Science 235 (2004) 31–41; henceforth “Bhaumik”).
Regarding claim 1, Ross discloses a method comprising contacting an isolated organ with a liquid (deionized water para. [0060]) (instant claim 1), which is a method of decellularizing an isolated organ or portion thereof (“Exemplary Perfusion Decellularization of Liver” para. [0060-0061]), wherein:
the liquid comprises a detergent (1% SDS para. [0060]).
However, regarding claim 1, Ross does not specifically teach that the liquid is at least partially degassed.
Nevertheless, regarding claim 1, Ross teaches the method comprises perfusion decellularization (“Exemplary Perfusion Decellularization of Liver” para. [0060-0061]).
Additionally, regarding claim 1, Guyette teaches bubbles should be prevented in the perfusion line for perfusion decellularization methods (“prevent air bubbles in the perfusion line” pg. 1454; see also pg. 1456 “Porcine and human organ preparation” step 7). Guyette teaches air bubbles can prevent adequate perfusion, and they can cause tissue damage if they are introduced into the organ vasculature (pg. 1460; step 11).
Moreover, regarding claim 1, Bhaumik teaches degassing deionized water with membrane degasification to achieve near complete removal of dissolved gases, CO2 and O2 (abstract; see also Figure 2 and 6).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Ross, and combine the known prior art element of the degasification of Bhaumik to obtain the predictable result of degassed deionized liquid. One of ordinary skill would have been motivate to do so as taught by Guyette to prevent air bubbles in the perfusion line (“prevent air bubbles in the perfusion line” pg. 1454; see also pg. 1456 “Porcine and human organ preparation” step 7). Regarding the reasonable expectation of success, Bhaumik evidences degassing deionized water with membrane degasification to achieve near complete removal of dissolved gases, CO2 and O2 (abstract; see also Figure 2 and 6).
Regarding claim 1, concerning the limitation that “the at least partially degassed liquid contains 80% or less of dissolved gas content compared to a non-degassed liquid,” the membrane degasification step made obvious by Bhaumik results in near complete removal of dissolved gases, CO2 and O2 (abstract; see also Figure 2; see in particular Figure 6 and pg. 36 col. 1). Therefore, it would have been obvious to a person of ordinary skill that degassed liquid suggested by Ross in view of Guyette and Bhaumik would have almost complete removal of dissolved gases, CO2 and O2, which is encompassed by the claimed range of 80% or less of dissolved gas content compared to a non-degassed liquid.
Regarding claims 4-6, further to the discussion of claim 1 above, Ross teaches the isolated liver organ is from a non-human mammal (instant claims 4-5), which is a pig (“pig decellularized organ” para. [0067] and Figure 1 para. [0025-0026] “porcine liver that was perfusion decellularized”) (instant claim 6).
Regarding claim 8, further to the discussion of claim 1 above as stated above, the isolated organ taught by Ross is the Liver (“Exemplary Perfusion Decellularization of Liver” para. [0060] see also para. [0003, 0006, 0014, 0016, 0021, 0023, 0025-0029, 0043-0045, 0061, 0083, 0086-0087, 0089, 0100, 0101, 0109, 0111]; claim 2).
Regarding claim 9, further to the discussion of claim 1 above, Ross discloses the contacting comprises (i) perfusing the liquid in the isolated organ (para. [0060-0061]).
Regarding claim 10, further to the discussion of claim 1 above, Ross discloses that prior to the contacting, the isolated organ is cannulated (“canulated using a mouse aortic canula” para. [0060]).
Regarding claim 12, further to the discussion of claims 1 and 11 above, the decellularized liver taught by Ross comprises an extracellular matrix (“perfusion decellularized organ- or tissue-derived extracellular matrix (ECM)” para. [0003]; see also para. [0004-0005, 0009-0019, 0021, 0034-0039, 0047-0050, 0057, 0059, 0070, 0077, 0081, 0083, 0105, 0110]).
Regarding claim 13, further to the discussion of claims 1 and 11-12 above, the extracellular matrix taught by Ross comprises a vasculature bed (“intact vasculature” para. [0039]).
Regarding claim 14, further to the discussion of claims 1 and 11-13 above, the vasculature bed taught by Ross remains intact following the contacting (“intact vasculature” para. [0039]).
Regarding claim 15, further to the discussion of claim 1 above, it is noted that instant claims are directed to only an “increased” compressive modulus, not an increase of a particular amount. Therefore, even a small increase would meet instant claims and this small amount of increase encompasses regular variation of compressive modulus that would occur in decellularization methods and would obviously be met by the combination above of Ross in view of Guyette and Bhaumik.
Additionally, regarding claim 15, Applicant’s claim encompasses a comparison to any “non-degassed liquid.” The broadest reasonable interpretation of this is any liquid that has the structure of not being partially degassed, such as pure sulfuric acid, which dissolves tissue and would therefore result in a lower compressive modulus than the ECM of Ross in view of Guyette and Bhaumik
Regarding claim 17, further to the discussion of claim 1 above, Ross discloses the isolated liver organ is contacted by the at least particularly degassed liquid (1% SDS in deionized water) for at least 2 hours (“2-12 hours of perfusion” para. [0060]).
Regarding claims 18 and 64, further to the discussion of claim 1 above, as stated above (see claim 1 rejection above), the membrane degasification step made obvious by Bhaumik results in near complete removal of dissolved gases, CO2 and O2 (abstract; see also Figure 2; see in particular Figure 6 and pg. 36 col. 1). Bhaumik specifically teaches the membrane degasification step results in concentrations of O2 at a level of 50 ppb and less (pg. 36 col. 1) and concentrations of 425 ± 10 ppm of CO2 (pg. 36 col. 1), which are both encompassed by the claimed range of less than 1 mg/mL (instant claim 18) and the range of less than 1 milligram per liter (instant claim 64).
Furthermore, regarding claims 18 and 64, the claim only requires that the at least partially degassed liquid has a concentration of less than about 1 mg/mL (instant claim 18) or less than 1 milligram per Liter (instant claim 64) of a dissolved gas, which could also be any dissolved gas, such as, for example nitrous oxide gas, which is also not present in the deionized water taught by Ross in the suggested method.
Regarding claims 19 and 66, further to the discussion of claims 1 and 18 above, as stated above (see claims 1 and 18 rejection above), the dissolved gas removed in the degasification step suggested by Bhaumik comprises O2 (instant claim 66) and CO2 (instant claims 19 and 66) (abstract; see also Figure 2; see in particular Figure 6 and pg. 36 col. 1).
Regarding claim 20, further to the discussion of claim 1 above, it is noted that instant claims are directed to only “fewer” air emboli or microbubbles and “less” pigmentation, not a reduction of a particular amount. Therefore, even a small reduction would meet instant claims and this small amount of reduction encompasses regular variation of air emboli, microbubbles, or pigmentation amounts that would occur in decellularization methods and would obviously be met by the combination above of Ross in view of Guyette and Bhaumik.
Furthermore, regarding claim 20, because Bhaumik makes obvious degassing the liquid, there would be less dissolved gas in the liquid which would obviously result in less bubbles.
Regarding claim 21, further to the discussion of claim 1 above, it is noted that instant claims are directed to only “reduced” residual DNA compared to an isolated organ or portion thereof that has not been contacted with the liquid, not a reduction of a particular amount. Therefore, even a small reduction would meet instant claims and this small amount of reduction encompasses regular variation of residual DNA amounts that would occur in decellularization methods and would obviously be met by the combination above of Ross in view of Guyette and Bhaumik.
Regarding claim 40, further to the discussion of claim 1 above, Ross teaches washing the isolated organ with a wash media prior to the contacting (“submerged in sterile PBS” para. [0060-0061]).
Regarding claims 63 and 65, concerning the limitation that the at least partially degassed liquid contains 50% (instant claim 63) or 20% (instant claim 65) or less of dissolved gas content compared to a non-degassed liquid,” as stated above (see claim 1 rejection above) the membrane degasification step made obvious by Bhaumik results in near complete removal of dissolved gases, CO2 and O2 (abstract; see also Figure 2; see in particular Figure 6 and pg. 36 col. 1). Therefore, it would have been obvious to a person of ordinary skill that degassed liquid suggested by Ross in view of Guyette and Bhaumik would have almost complete removal of dissolved gases, CO2 and O2, which is encompassed by the claimed range of 50% or less (instant claim 63) or 20% or less (instant claim 65) of dissolved gas content compared to a non-degassed liquid.
Furthermore, regarding claims 1, 18, 63 and 65, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Lastly, regarding claims 1, 18, 63 and 65, Applicant is reminded that generally, differences in concentration will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical (MPEP 2144.05 II). Moreover, at the time of the claimed invention, one of ordinary skill in the art would have been motivated by routine practice to optimize the concentration of dissolved gas in the liquid.
Hence, the claimed invention as a whole was prima facie obvious.
Response to Arguments
Applicant’s arguments, filed 10th, August, 2026, have been fully considered but are not found persuasive.
Analogous Art
Applicant argues “Bhaumik is Non-Analogous Art” (pg. 10-11). Specifically, Applicant argues Bhaumik satisfies neither test for analogous art (Pg. 11). Applicant argues “Bhaumik is not in the same field of endeavor as the claimed invention. Bhaumik is directed to hollow fiber membrane degassing in the production of ultrapure water (UPW) for the microelectronics industry” and “The claimed invention, by contrast, is directed to methods of decellularizing an isolated organ or portion thereof - a field within tissue engineering and regenerative medicine that bears no relation to semiconductor manufacturing or the purification of industrial process water. The two fields of endeavor are wholly unrelated” (pg. 11). Applicant argues “Bhaumik is not reasonably pertinent to the particular problem with which the inventor was concerned. The problem addressed by the claims is how to improve the decellularization of an isolated organ while preserving the integrity of its extracellular matrix and vasculature. Bhaumik is concerned with an entirely different problem - removing dissolved gases (and controlling microbiocontamination) in industrial ultrapure water systems so that the water is suitable for rinsing semiconductor wafers (pg. 11).
In response, as cited by Applicant (pg. 10), 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). 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.
Field of Endeavor
In this case, Bhaumik is analogous art because Bhaumik is drawn to methods of production of ultrapure water. Ultrapure water is commonly used in biological laboratories for a variety of applications, such preparation of buffer solutions or such as in preparation of decellularization solutions and therefore ultrapure water references are in the same field of endeavor as decellularization methods.
To complete the art of record and to rebut Applicant’s arguments, Applicant is directed to the art of Chen et al. (Methods Mol Biol. 2018;1577:255–270.; henceforth “Chen”). Chen teaches a method of preparation of decellularized liver scaffolds (Methods pg. 8-9 “3.2 Perfusion Decellularization”). Chen specifically teaches the solutions used in the method are prepared with ultrapure water (“Solutions are prepared with ultrapure water” Materials pg. 2). Therefore, Chen evidences methods relating to ultrapure water are analogous art to decellularization methods because ultrapure water is used in the art for preparing solutions for perfusion decellularization.
Bhaumik is also analogous art because the instantly claimed method includes degasification steps and therefore includes the field of endeavor of degasification, and Bhaumik is drawn to membrane degasification, which is in the same field of endeavor of degasification.
Reasonably Pertinent
The reference of Bhaumik is also analogous art because it is reasonably pertinent. MPEP 2141.01 (a) states that for the "reasonably pertinent" test, the examiner should consider the problem faced by the inventor, as reflected - either explicitly or implicitly - in the specification. In order for a reference to be "reasonably pertinent" to the problem, it must "logically [] have commended itself to an inventor's attention in considering his problem." In re ICON Health and Fitness, Inc., 496 F.3d 1374, 1379-80 (Fed. Cir. 2007) (quoting In re Clay, 966 F.2d 656,658, 23 USPQ2d 1058, 1061 (Fed. Cir. 1992)). See also In re Klein, 647 F.3d 1343, 1348, 98 USPQ2d 1991, 1993 (Fed. Cir. 2011) An inventor is not expected to have been aware of all prior art outside of the field of endeavor. Airbus, 41 F.3d at 1380-82. A reference outside of the field of endeavor is reasonably pertinent if a person of ordinary skill would have consulted it and applied its teachings when faced with the problem that the inventor was trying to solve. Airbus, 41 F.3d at 1380-82.
MPEP 2141.01 (a) further states that, in evaluating the applicant's argument, the examiner should look to the teachings of the specification and the inferences that would reasonably have been drawn from the specification by a person of ordinary skill in the art as a guide to understanding the problem to be solved.
While Applicant argues “The problem addressed by the claims is how to improve the decellularization of an isolated organ while preserving the integrity of its extracellular matrix and vasculature” (pg. 11), this appears to be a more narrow problem than what is taught by the instant specification. The instant specification does not explicitly use the word “problem,” but the specification does refer to “improved decellularization” (see Title; para. [0031, 0041, 0062, 0118, 0120, 0121]). Therefore, because the specification appears to be drawn more generally to improvement of decellularization, arts which include methods of decellularization and their components would be considered “reasonably pertinent” to this problem. As stated above, the art of Chen evidences ultrapure water can be used in the art to prepare solutions for perfusion decellularization and therefore methods of preparing ultrapure water would be reasonably pertinent to preparing solutions for perfusion decellularization and therefore would also be reasonably pertinent to methods of improving perfusion decellularization.
Motivation to Combine
Applicant argues “In this case, the Examiner has failed to advance a reason why the skilled artisan in the field of tissue engineering would have combined the teachings of Bhaumik- relating to ultrapure water for use in the microelectronics industry - in a method of decellularizing an isolated organ as disclosed in Ross with any reasonable likelihood of success.” (pg. 10).
Applicant argues “there can be no rational underpinning for why the skilled artisan would look to the ultrapure water used in the microelectronics industry to arrive at a degassed liquid comprising a radical-generating compound or detergent for the purpose of decellularizing an isolated organ or portion thereof. Therefore, the combination of cited references could not have afforded a person of ordinary skill in the art any reasonable expectation of achieving the results obtained by the claimed methods.” (pg. 10)
Applicant argues “A Person of Ordinary Skill Would have had no Motivation to Combine” (pg. 12). Applicant argues “Bhaumik provides no motivation for a person of ordinary skill in the art to select the liquid it describes for use in a method of decellularizing an organ. Bhaumik' s degassing is performed for the sole purpose of producing ultrapure water for semiconductor manufacturing, using commercially available blood oxygenator membrane modules under vacuum to strip CO2 and 02 from deionized water. Given this entirely unrelated technical context, a skilled artisan seeking to decellularize an organ would have had no reason to consult Bhaumik at all, let alone to adopt its degassed water in an organ
decellularization protocol. Guyette's generalized concern with preventing air bubbles in a
perfusion line does not supply the missing motivation, because nothing in Guyette or Ross would
have directed the skilled artisan to Bhaumik' s ultrapure-water process as a solution” (pg. 12).
In response, it is first noted that the radical-generating compound and combination including the radical-generating compound are currently unelected species and are not currently under consideration.
Further in response, the grounds of rejection above is based on the combined teaching of Ross, Guyette, and Bhaumik. As set forth in the grounds of rejection above, Guyette specifically teaches removing air bubbles in perfusion lines and provides a motivation for a person of ordinary skill to want to remove bubbles from perfusion lines. Since the primary reference of Ross includes perfusion lines, this teaching to remove bubbles to improve the method of Ross would be obvious as set forth above. Once removing bubbles is made obvious, a person of ordinary skill would look to the information available in the art to remove air bubbles from the solution of the Primary reference of Ross. The motivation provided to is to remove bubbles which is taught by Guyette. Using the method of Bhaumik to degas the solution in order to remove the bubbles is at least a rationale of MPEP 2143 Exemplary rationale (A) of “Combining prior art elements according to known methods to yield predictable results.”
Applicant is directed to MPEP 2143 (A) which sets the criteria for Exemplary Rationale (A):
A. Combining Prior Art Elements According to Known Methods To Yield Predictable Results
To reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
(1) a finding that the prior art included each element claimed, although not necessarily in a single prior art reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference;
(2) a finding that one of ordinary skill in the art could have combined the elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately;
(3) a finding that one of ordinary skill in the art would have recognized that the results of the combination were predictable; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
Concerning (1), as set forth above, the prior art included each element claimed in the references of Ross and Bhaumik.
Concerning (2), one of ordinary skill could have combined the membrane degasification steps of Bhaumik to the solution of Ross and it would degas the solution or Ross and therefore it performs the same function as it does separately.
Concerning (3), a person of ordinary skill would have recognized that the results of the combination were predictable because the method of degassing of Bhaumik works on water and therefore would be expected to work on the decellularization media of Ross.
Concerning (4), as set forth above, Guyette provides motivation to specifically make this combination by teaching that bubbles are undesirable in perfusion, and membrane degasification is known to remove bubbles.
In order to complete the art of record and rebut Applicant’s arguments, Applicant is directed to the art of Liu et al. (Lab Chip. 2011 Mar 28;11(9):1688–1693.; henceforth “Liu”). Liu evidences that membrane degasification is known in the art to remove bubbles from flow streams (see “membrane-based debubbler that can be readily incorporated into microfluidic devices for rapid degassing” abstract; see also “Once the air bubble reaches the membrane (Fig. 3a iii), it permeates through the membrane. Downstream of the membrane, the fluid is completely bubble-free (Fig. 3a iv)”).
Therefore, one of ordinary skill would have taken the teaching of Guyette that bubbles are undesirable in perfusion system, looked to apply a way to remove bubbles from the perfusion system of Ross, arrived at known methods in the art of membrane degassers which are known to remove bubbles including the teachings of Bhaumik for a way to achieve near complete removal of dissolved gases (as set forth above), which would be superior because it has near complete removal.
Applicant is directed to MPEP 2143 which states that the key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. MPEP 2143 further states that in Ball Aerosol v. Ltd. Brands, 555 F.3d 984, 89 USPQ2d 1870 (Fed. Cir. 2009), the Federal Circuit offered additional instruction as to the need for an explicit analysis. The Federal Circuit explained that the Supreme Court’s requirement for an explicit analysis does not require record evidence of an explicit teaching of a motivation to combine in the prior art.
In the instant case, a person of ordinary skill would find that the instantly claimed invention is prima facie obvious as set forth above.
Concerning Applicant’s arguments about the art applied in the rejection being from “entirely unrelated technical context” the art of Bhaumik as analogous art is addressed above.
Concerning Applicant’s argument that “Bhaumik provides no motivation for a person of ordinary skill in the art to select the liquid it describes for use in a method of decellularizing an organ” it is noted that in the grounds of rejection above, it is the method step of degassing of Bhaumik that is combined, and not the specific liquid, and the degassing step of Bhaumik is made obvious for the reasons set forth above.
Hindsight Reasoning
Applicant argues “The proposed combination is instead the product of impermissible hindsight reconstruction using Applicant's own disclosure as a template” (pg. 12).
Applicant argues “The combined teachings do not render this claim obvious, as assembling them requires impermissible hindsight to select specific, disjointed elements from the prior art.” (pg. 13).
In response, as fully set forth above, in the grounds of rejection above, each element of the claims is specifically addressed.
Applicant is directed to MPEP 2142 which states that 35 U.S.C. 103 authorizes a rejection where, to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references. "To support the conclusion that the claimed invention is directed to obvious subject matter, either the references must expressly or impliedly suggest the claimed invention or the examiner must present a convincing line of reasoning as to why the artisan would have found the claimed invention to have been obvious in light of the teachings of the references." Ex parte Clapp, 227 USPQ 972, 973 (Bd. Pat. App. & Inter. 1985). The rejection of record above provides a convincing line of reasoning as to why the artisan would have found the claimed invention to have been obvious in light of the teachings of the references and therefore the preponderance of the evidence is that the combined teachings render the claimed invention obvious.
Applicant is further directed to MPEP 2145 (X)(A) which states that "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). In the instant case, because the each of the claimed elements is made obvious by the combination as set forth above, which takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made, the reconstruction is proper.
Applicants remaining arguments concerning the combination are addressed specifically above and below.
Applicant argues “Guyette Teaches Prevention of Air Bubbles in the Perfusion Line, Not the Use of a Degassed Liquid” (pg. 12). Specially, Applicant argues “Guyette does not teach or suggest that the perfusion liquid must be degassed” and “This is a teaching about removing or excluding discrete gas pockets (e.g.: air bubbles) from the perfusion line itself Guyette says nothing about the concentration of dissolved gas in the perfusion liquid, and it does not direct the skilled artisan to degas that liquid” (pg. 13). Applicant argues “degassed liquid and a bubble-free perfusion line are fundamentally different things. As reflected in the Specification, a liquid is "degassed" when its dissolved gas content - for
example, dissolved oxygen, nitrogen, or carbon dioxide - has been substantially removed from
the liquid itself The removal of air bubbles from a perfusion line, by contrast, is a mechanical or
procedural measure that addresses discrete gas pockets already present within the tubing or
apparatus. Instead, Guyette operates on the line, not on the dissolved-gas content of the liquid.
The point is confirmed by the art of record. Dolan explains that even where degassing devices
reduce the total dissolved-gas burden of a liquid, "dissolved air still remains," and, conversely,
that a liquid may be free of visible bubbles yet still carry substantial dissolved gas that can
subsequently evolve out of solution. Bubble-free operation and degassing are therefore addressed
to different phenomena and are not interchangeable.” (pg. 13). Applicant argues “It follows that removing bubbles from a perfusion line does not result in a degassed liquid. Clearing discrete air pockets from the tubing does not remove the gases dissolved in the perfusion liquid itself Indeed, a perfusion line that has been rendered free of visible bubbles may still be filled with a liquid that is fully gas-saturated. Accordingly, achieving a bubble-free perfusion line, as Guyette describes, does not render the perfusion liquid "at least partially degassed," and Guyette' s teaching regarding bubble prevention cannot supply the degassed liquid limitation recited in the claims, which is a limitation the Office concedes is absent from Ross and for which the Office turns solely to Bhaumik. Because Guyette does not teach, suggest, or provide a reason to degas the perfusion liquid, it neither cures the deficiencies of Ross and Bhaumik nor supplies a motivation to arrive at the claimed methods” (pg. 12).
In response, As stated above, the rejection is based on the combined teachings of Ross, Guyette and Bhaumik. In response, as stated above, Guyette is relied upon for the teaching that bubbles are undesirable Because Ross uses perfusion lines, one of ordinary skill would see the teaching of Guyette that removing bubbles would be an advantage in the method of Ross. As set forth above, the specific membrane degasser of Bhaumik would represent a combination of known prior art elements to achieve predictable results and would also have the specific advantage of near complete gas removal.
Reasonable Expectation of Success and Alleged Advantages
Applicant argues “The Skilled Artisan Would not have had a Reasonable Expectation of Improving Organ Decellularization Using a Degassed Liquid” (pg. 13-14). Applicant argues “a person of ordinary skill in the art would not have reasonably expected the liquid described in Bhaumik, when used in a method of decellularizing an organ, to yield the results achieved by the claimed methods. As the Specification explains, decellularization is a complex and unpredictable undertaking, and the use of an at least partially degassed liquid confers a constellation of benefits that a skilled artisan would not have predicted from a reference concerned only with industrial water purification. Applicant's Specification, at paragraph [0002].” (pg. 13). Applicant specifically argues “as described in the Specification at paragraphs [0076]-[0080] and [0083], contacting an isolated organ or portion thereof with an at least partially degassed liquid provides, relative to an otherwise comparable non-degassed liquid: (i) fewer air emboli, fewer microbubbles, and less pigmentation; (ii) an extracellular matrix having an increased
compressive modulus; and (iii) improved preservation of the vasculature, such that the
vasculature bed remains at least partially intact following the contacting. These are not properties
of the degassed deionized water disclosed in Bhaumik - which is never brought into contact with
any tissue - but rather are advantages realized only when a degassed liquid is employed in the
specific context of organ decellularization. Nothing in Bhaumik, Ross, or Guyette teaches or
suggests these outcomes, and a skilled artisan would not reasonably have expected them.” (pg. 14).
Applicant further argues “As further demonstrated in Examples 2 and 6 of the Specification, decellularization using degassed media proceeds more efficiently, in less time, and using less volume of media than decellularization using otherwise comparable non-degassed media, thereby achieving more
complete decellularization while better preserving the organ's vascular structures. A skilled artisan reading Bhaumik would have had no basis to expect that substituting a degassed liquid in an organ decellularization method would improve the efficiency or completeness of decellularization or enhance preservation of the vasculature” (pg. 14).
First, concerning Applicant’s arguments, the reasonable expectation of success applies to the invention as claimed. The recited advantages are not required by instant claims, and therefore a reasonable expectation of success it not required for these advantages. 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).
Further in response, Applicant is directed to MPEP 2143.02 which states that where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success. The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016). In other words, while the prior art suggests the reason for modification, it is the preparation of the modification that requires a reasonable expectation of success. Achievement of the desired result is not necessarily required. In the instant case, Bhaumik provides a reasonable expectation of success in combining or modifying prior art disclosures to meet the limitations of the claimed invention because Bhaumik evidences membrane degasification in water and therefore a person of ordinary skill would have had a reasonable expectation of success using the membrane degasification to degas the decellularization media of Ross. Applicant’s specific recited advantages are not a requirement of all of instant claims and therefore the reasonable expectation of success if met by evidence of Bhaumik that one of ordinary skill could prepare the structural requirements of the degassed liquid, and evidence of a reasonable expectation of success for the advantages cited by Applicant is not required. Furthermore, the specific advantages and reasonable expectation of success of those specific recited advantages of claims 20-21 are discussed in the grounds of rejection above.
Furthermore, Applicant is reminded that conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")).
Further in response, concerning Applicant’s alleged advantages as a potential unexpected result, this is not found persuasive for several reasons.
Applicant argues the following advantages:
“Applicant's Specification, at paragraph [0002].” (pg. 13). Applicant specifically argues “as described in the Specification at paragraphs [0076]-[0080] and [0083], contacting an isolated organ or portion thereof with an at least partially degassed liquid provides, relative to an otherwise comparable non-degassed liquid: (i) fewer air emboli, fewer microbubbles, and less pigmentation; (ii) an extracellular matrix having an increased compressive modulus; and (iii) improved preservation of the vasculature, such that the vasculature bed remains at least partially intact following the contacting” (pg. 14).
“As further demonstrated in Examples 2 and 6 of the Specification, decellularization using degassed media proceeds more efficiently, in less time, and using less volume of media than decellularization using otherwise comparable non-degassed media, thereby achieving more
complete decellularization while better preserving the organ's vascular structures” (pg. 14).
In response to Applicant’s arguments, arguments of counsel cannot take the place of factually supported objective evidence in the record. See In re Schulze, 346 F.2d 500, 602, 145 USPQ 716, 718 (CCPA 1965), In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Thus, Attorney statements regarding the unexpected result are not evidence without a supporting declaration. Specifically, Applicant has not provided objective scientific evidence on the record that the results of fewer air emboli, fewer microbubbles, and less pigmentation; (ii) an extracellular matrix having an increased compressive modulus; and (iii) improved preservation of the vasculature as well as efficiency and more complete decellularization while better preserving the organ's vascular structures is facilitated over prior art methods.
Concerning the alleged unexpected results, the burden is on the Applicant to establish results are unexpected and significant (MPEP 716.02(b)(I)), Applicants have the burden of explaining the proffered data (and MPEP 716.02(b)(II)), and the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support (MPEP 716.02(d)(I)).
The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c) (MPEP 716.02(b)(I)). Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). See In re Blondel, 499 F.2d 1311, 1317, 182 USPQ 294, 298 (CCPA 1974) and In re Fouche, 439 F.2d 1237, 1241-42, 169 USPQ 429, 433 (CCPA 1971) for examples of cases where indirect comparative testing was found sufficient to rebut a prima facie case of obviousness. (MPEP 716.02(b)(II)).
In the instant case, Applicant’s advantages (alleged unexpected results) are insufficient to overcome the rejection of record under 35 U.S.C. 103 for several reasons. First, as discussed above, the alleged unexpected results are not supported by factually objective evidence on the record. Next, the data cited by Applicant (Examples 2 and 6 cited above) appears to be compared to a control and is not compared to the closest prior art. Because the data cited by Applicant is not compared to the closest prior art, the statistical and practical significance of the date (required by MPEP 716.02(b)(II); see above) are not apparent. Finally, the alleged unexpected results do not appear to be in scope with the claimed invention, as the cited results appear to correspond to the specific unelected organ of a kidney (example 2) and the unelected radical generating compound (in Example 6). The Examples also appear to require a specific amount of degassing and specific buffers (see Example 1), which is much narrower than instant claims. Additionally, because Applicant argues that “decellularization is a complex and unpredictable undertaking”(pg. 14) these results cannot be construed to the full breadth of instant claims.
It is further noted that Example 6 requires the combination of the radical generating compound which is an unelected species that is not currently under consideration.
Withdrawn Claim Rejections - 35 USC § 103
The rejection of claims 1, 4-6, 8-9, 21, 40, 63 and 65 under 35 U.S.C. 103 as being unpatentable over Choi et al. (Ultrasound Med Biol. 2011 Dec;37(12):2000-12.; see IDS filed 26th, October, 2021; henceforth “Choi”) in view of Dolan (2014, accessed at: https://www.chromatographyonline.com/view/mobile-phase-degassing-what-why-and-how) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
No claim is allowable.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIANA N EBBINGHAUS whose telephone number is (703)756-4548. The examiner can normally be reached M-F 9:30 AM to 5:30 PM ET.
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, Peter Paras can be reached at (571) 272-4517. 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.
/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632
/EMILY A CORDAS/Primary Examiner, Art Unit 1632
Prosecution Insights