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
Claims 1, 4-15, 17-21, 25-27, 40 and 63-70 are pending.
Claims 7, 25-27, and 69-70 are withdrawn.
Claims 1, 4-6, 8-15, 17-21, 40 and 63-68 are under examination.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8th, January, 2026 has been entered.
Election/Restrictions
Note that newly submitted claim 69-70 are 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 claims 69-70 are 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Accordingly, claims 69-70 are withdrawn from consideration as being directed to a non-elected species. See 37 CFR 1.142(b) and MPEP § 821.03.
Claims 1, 4-6, 8-15, 17-21, 40 and 63-68 are under examination.
Claim Interpretation
It is noted that the instant specification states “a "degassed" cellular disruption media can refer to a disruption media as described herein, where a dissolved gas has been substantially removed” (pg. 21).
Instant claims are drawn to a method including liquid that is “at least partially degassed” which is product by process language with respect to the liquid. It is noted that instant claims do not currently require a step of degassing the liquid. Applicant is reminded that product-by process claims are not limited by the manipulation of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (see MPEP 2113). In the instant case, a liquid that is structurally identical to an “at least partially degassed” liquid, which otherwise meets recited claim limitations, will meet instant claims.
Claim Rejections - 35 USC § 112(a)
Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4-6, 8-15, 17-21, 40 and 63-68 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ) first paragraph.
Regarding claims 1, 4-6, 8-15, 17-21, 40 and 63-66, the specification, while being enabling for:
A method comprising contacting an isolated organ or portion thereof with a liquid, wherein:
the liquid is at least partially degassed, wherein the at least partially degassed liquid
contains 80% or less of dissolved gas content compared to a non-degassed liquid; and
the liquid comprises a detergent, a radical-generating compound, or both; or
the liquid comprises a detergent, a radical-generating compound, or both and the isolated organ or portion thereof is from a mammal that was fed within about ten hours prior to removal of the isolated organ or portion thereof
does not reasonably provide enablement for:
A method comprising contacting an isolated organ or portion thereof with a liquid, wherein:
the liquid is at least partially degassed, wherein the at least partially degassed liquid
contains 80% or less of dissolved gas content compared to a non-degassed liquid; and
the isolated organ or portion thereof is from a mammal that was fed within about ten hours prior to removal of the isolated organ or portion thereof, thereby forming an at least partially decellularized isolated organ or portion thereof.
Specifically, regarding claims 1, 4-6, 8-15, 17-21, 40 and 63-66, the specific functional result of “forming an at least partially decellularized isolated organ or portion thereof, which is specifically recited in claim 11 which is encompassed by the claim 1 and its dependents, is not enabled without including that the limitation that the liquid comprises a detergent, a radical-generating compound, or both.
Regarding claims 67-68, the specification, while being enabling for:
A method of decellularizing an isolated organ or portion thereof comprising contacting the isolated organ or portion thereof with a at least partially degassed liquid, wherein:
the liquid comprises a detergent, a radical-generating compound, or both; or
the liquid comprises a detergent, a radical-generating compound, or both and the isolated organ or portion thereof is from a mammal that was fed within about ten hours prior to removal of the isolated organ or portion thereof.
does not reasonably provide enablement for:
A method of decellularizing an isolated organ or portion thereof comprising contacting the isolated organ or portion thereof with a at least partially degassed liquid, wherein:
(b) the isolated organ or portion thereof is from a mammal that was fed within about ten hours prior to removal of the isolated organ or portion thereof.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the method of the invention commensurate in scope with these claims.
Wands Factors
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
Breadth of the Claims
Regarding claims 1, 4-6, 8-15, 17-21, 40 and 63-66, Instant claims encompass:
Methods comprising contacting an isolated organ or portion thereof with a liquid, wherein: the liquid is at least partially degassed, wherein the at least partially degassed liquid contains 80% or less of dissolved gas content compared to a non-degassed liquid; and the isolated organ or portion thereof is from a mammal that was fed within about ten hours prior to removal of the isolated organ or portion thereof”
This encompasses methods of contacting wherein the isolated organ or portion thereof with all possible at least partially degassed liquids that liquid contain 80% or less of dissolved gas content compared to a non-degassed liquid and requires the functional result of “forming an at least partially decellularized isolated organ or portion thereof” of the thereby clause of instant claim 11 and is encompassed by claim 1 and its dependents.
Regarding claims 67-68, Instant claims encompass:
Methods of decellularizing an isolated organ or portion thereof comprising contacting the isolated organ or portion thereof with a at least partially degassed liquid wherein the isolated organ or portion thereof is from a mammal that was fed within about ten hours prior to removal of the isolated organ or portion thereof.
This encompasses methods of contacting wherein the isolated organ or portion thereof with all possible at least partially degassed liquids and requires the functional result of “decellularizing” of the instant preamble.
Direction or Guidance Presented
While contemplating methods comprising decellularizing an isolated organ or portion thereof comprising contacting the isolated organ or portion thereof with a at least partially degassed liquid wherein the isolated organ or portion thereof is from a mammal that was fed within about ten hours prior to removal of the isolated organ or portion thereof, Applicant provides limited guidance on methods of decellularizing that appear to require either a detergent, a radical-generating compound, or both to arrive at the result of decellularizing.
Present Working Examples
The elements of working examples considered pertinent to the present rejection are summarized below.
Example 1 (para. [0071-0086])
In Example 1, degassed decellularization solution was used which contains a detergent (para. [0074]), a detergent and a radical generating compound (Triton X and ammonium hydroxide; para. [0079, 0084]), degassed PEG (para. [0077]), or degassed water with a detergent (SDS; para. [0081-0082])
Example 4 (para. [0101])
In Example 4, isolated livers from non-fasted pig animals were decellularized with a decellularization solution of 500 ml water containing 1% SDS (para. [0106]).
Example 5 (para. [0116-0117])
In Example 5, isolated livers were decellularized with a solution of Peracetic acid in saline solution.
Example 6 (para. [0118-0119])
In Example 6, PAA was used as a radical generating compound to decellularize an isolated pig liver.
Example 7 (para. [0120])
In Example 7, an isolated mammalian liver was decellularized using solutions with SDS, followed by a solution with PAA, followed by a solution with PAA in SDS.
Example 8 (para. [00121-0122])
In Example 8, an isolated mammalian liver was decellularized in the presence or absence of PAA as described in Example 7.
Absent Working Examples
Importantly, there is no specific guidance or working examples of decellularizing without using a solution comprising a detergent, a radical-generating compound, or both, which is encompassed by instant claims.
State of the Art and Unpredictability of the Art
Mendibil
Regarding the liquids, Applicant is directed to the art of Mendibil et al. (Int J Mol Sci. 2020 Jul 30;21(15):5447.; henceforth “Mendibil”). Mendibil teaches that most protocols describe combinatorial and sequential use of different physical, chemical, and enzymatic techniques in order to achieve tissue-specific decellularization, with chemical and enzymatic techniques mainly responsible for successful decellularization in most protocols (pg. 4 last para.).
Therefore, because chemical and enzymatic techniques are required for decellularization, Applicant is not enabled for methods using degassed liquids that do not also include chemical and enzymatic components for decellularization.
Choi
Regarding the liquids, Applicant is additionally directed to the art of record of Choi et al. (Ultrasound Med Biol. 2011 Dec;37(12):2000-12.; see IDS filed 26th, October, 2021; henceforth “Choi”). Choi teaches A method comprising contacting an isolated organ or portion thereof with a liquid, wherein: the liquid is at least partially degassed (“properly cut piece of liver slice was degassed in PBS” pg. 2001 and “liver samples was placed into the sample holder along with degassed PBS buffer” pg. 2002”). However, the method of Choi does not appear to result in decellularized tissue.
Unpredictability of the Art and the Quantity of Experimentation Necessary
As the arts of Mendibil and Choi demonstrate, the obstacles that hinder the use of the claimed method are not easy tasks to be done or solely routine experimentation to enabled particular embodiments of the claimed method. The type of experimentation would require new methodologies. This level of experimentation goes beyond what would be routine optimization know at the time of filing. As such, the amount of experimentation would be undue.
The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112(a) requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to practice the instant claimed invention.
Scope of Enablement - Conclusion
In conclusion, the breadth of the claims lack enablement because the specification provides limited working examples which each utilize a detergent, radical generating compound of both in the degassed liquid, while instant claims encompass all possible degassed liquids. The art at the time of effective filing fail to provide specific guidance that supplement to shortcomings of the specification and further teaches that the breadth of claims cannot predictably be performed for methods that include other degassed liquids. Further, a great deal of new methodology would need to be developed to enable the full breadth of the claims and this level of experimentation is undue.
Withdrawn Claim Rejections - 35 USC § 112(a)
The rejection of claim 65 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement as set forth in the previous office action is withdrawn in view of Applicant’s amendments and arguments of record.
Withdrawn Claim Rejections - 35 USC § 112
Improper Markush
The rejection of claim 8 on the basis that it contains an improper Markush grouping of alternatives is withdrawn in view of Applicant’s arguments.
Withdrawn Claim Rejections - 35 USC § 112(b)
The rejection of claim 65 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.
New 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 18 and 21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 18 recites the limitation “less than about” with no corresponding special definition. Thus, there is nothing in the specification, prosecution or prior art to provide any indication as to the claimed range, thereby rendering the scope of the claim(s) unascertainable. See MPEP § 2173.05(b), III.A. Additionally, the phrase “less than” creates a hard upper cutoff for the value, but the term “about” indicates there is a range for the stated value. Including both “less than” and “about” makes it unclear whether or not the upper value is a hard cutoff for the range.
Claim 21 recites relative terminology “reduced.” A claim may be rendered indefinite when a limitation of the claim is defined by reference to an object and the relationship between the limitation and the object is not sufficiently defined. That is, where the elements of a claim have two or more plausible constructions such that the examiner cannot readily ascertain positional relationship of the elements, the claim may be rendered indefinite. See, e.g., Ex parte Miyazaki, 89 USPQ2d 1207 (Bd. Pat. App. & Inter. 2008) (precedential) and Ex parte Brummer, 12 USPQ2d 1653 (Bd. Pat. App. & Inter. 1989). In the instant case the required “reduced residual DNA” is dependent on some reference value of residual DNA which is not sufficiently defined (see MPEP 2173.05(b)).
New Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 11 is rejected 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.
Claim 11 recites “the liquid comprises an at least partially degassed decellularization media.” However, claim 1, upon which claim 11 depends, already recites “the liquid is at least partially degassed, wherein the at least partially degassed liquid contains 80% or less of dissolved gas content compared to a non-degassed liquid.” The recitation of “an at least partially degassed decellularization media” is broader than the liquid recited in claim 1, upon which claim 11 depends, because claim 1 recites the narrower “80% or less of dissolved gas content.” Therefore, because the “at least partially degassed decellularization media” of claim 11 is broader than the liquids with “80% or less of dissolved gas content” of claim 1, claim 11 cannot further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Withdrawn Claim Rejections - 35 USC § 102
The rejection of claims 1, 4-6, 8-15, 17-21, 40 and 63 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 withdrawn in view of Applicant’s amendments.
The rejection of claims 63-66 under 35 U.S.C. 102(a)(1) as being anticipated by Choi et al. (Ultrasound Med Biol. 2011 Dec;37(12):2000-12.; see IDS filed 26th, October, 2021; henceforth “Choi”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
New Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 67 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ross (US-2012/0064537-A1; see IDS filed 26th, October, 2021).
Regarding claim 67, Ross discloses a method of decellularizing an isolated organ (“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) comprising contacting an isolated organ with a liquid (deionized water para. [0060]), wherein:
the liquid comprises a detergent (1% SDS para. [0060])
Regarding claim 67, concerning the limitation that “the liquid is at least partially degassed” the deionized water of Ross meets the structural requirements of “at least partially degassed” for several reasons. A “partially” degassed liquid includes a liquid that has lost even one gas molecule of any type. Furthermore, instant claims do not require a specific type of gas removed, so this further includes a liquid that has had any possible type of gas, such as Nitrous Oxide, Ammonia, Hydrogen Fluoride, Xenon, Methane, or any other gas that one is capable of being dissolved in a liquid and is further capable of being removed from a liquid, even if only one gas molecule is removed (i.e. “partially” degassed of that gas). Because the “at least partially degassed” is a product by process limitation on the liquid, the liquid need only be structurally identical, but does not require a method step to be performed. In other words, the deionized water of Ross, which is structurally indistinct from deionized water that has had a gas such as Nitrous Oxide, Ammonia, Hydrogen Fluoride, Xenon, Methane, or any other gas that one is capable of being dissolved in a liquid that has been dissolved and subsequently removed, meets instant claims.
Accordingly, Ross anticipates instant claim.
Examiner’s Remark
The Examiner notes that the ground of rejection above under 35 U.S.C. 102 is a new grounds of rejection over a newly presented claim. For the sake of compact prosecution, arguments considered pertinent to the new grounds of rejection above are addressed below.
Response to Arguments
Applicant’s arguments, filed 12th, December, 2025 have been fully considered but are not found persuasive.
Applicant argues that “claims 67-70 are at least allowable for the same reasons as the
previously presented claims” (pg. 11). Applicant argues that the limitation of “80% or less of dissolved gas content compared to a non-degassed liquid” of the amendments overcomes the rejections (pg. 9).
In response, this is not found persuasive because this is not a limitation of claim 67, which is rejected above. Furthermore, as stated above, the deionized water of Ross, which is structurally indistinct from deionized water that has had a gas such as Nitrous Oxide, Ammonia, Hydrogen Fluoride, Xenon, Methane, or any other gas that one is capable of being dissolved in a liquid that has been dissolved and subsequently removed, meets instant claims for the reasons set forth above.
New 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, 8-15, 17-21, 40 and 63-68 are 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 claims 1 and 67, 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 (“Exemplary Perfusion Decellularization of Liver” para. [0060-0061]) (instant claim 67), wherein:
the liquid comprises a detergent (1% SDS para. [0060]).
However, regarding claim 1, Ross does specifically teach that the liquid is at least partially degassed.
Nevertheless, regarding claims 1 and 67, Ross teaches the method comprises perfusion decellularization (“Exemplary Perfusion Decellularization of Liver” para. [0060-0061]).
Additionally, regarding claims 1 and 67, 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 claims 1 and 67, 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 claims 1 and 67, 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 claims 1 and 68, 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 11, further to the discussion of claim 1 above, as stated above (see claim 1 rejection above), Ross discloses the liquid is 1% SDS in deionized water (para. [0060]), which is also a decellularization media because the 1% SDS in deionized water (para. [0060]) decellularizes tissue, and Ross teaches the method results in a decellularized isolated organ (“pig decellularized organ” para. [0067] and Figure 1 para. [0025-0026] “porcine liver that was perfusion decellularized”; see also para. [0060-0061]). As stated above (see claim 1 rejection above), Guyette and Bhaumik make obvious degassing the solution of Ross, and this combination would obviously result in a an at least partially degassed decellularization media for the reasons set forth above.
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 “about 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, 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, 65 and 68, 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, 65 and 68, Additionally, 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.
Claims 1, 4-6, 8-9, 21, 40, 63 and 65 are rejected 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).
Regarding claim 1, Choi discloses
A method comprising contacting an isolated organ or portion thereof with a liquid, wherein:
the liquid is at least partially degassed (“properly cut piece of liver slice was degassed in PBS” pg. 2001 and “liver samples was placed into the sample holder along with degassed PBS buffer” pg. 2002”; “degassed in PBS for 30 min by placing it in a vacuum chamber … at the setting of 76 cm Hg” pg. 2001 col. 2 Materials and Methods); and
Regarding claim 1 (b), Choi discloses porcine liver samples were collected from a slaughterhouse. Pigs from a slaughter house are either fasted, which means they haven’t been fed for a period of time prior to collection, or not-fasted, which means they have been fed prior to slaughter. One of ordinary skill would have immediately envisioned non-fasted conditions from the limited genus of two options, which would include the pigs having been fed within about ten hours.
Regarding claims 1, 63 and 65, although Choi teaches the liquid (PBS) is degassed by placing it in a vacuum chamber for 30 minutes (“degassed in PBS for 30 min by placing it in a vacuum chamber … at the setting of 76 cm Hg” pg. 2001 col. 2 Materials and Methods), Choi is silent to the percentage of dissolved gas in the degassed liquid.
Nevertheless, regarding claims 1, 63 and 65 , Dolan teaches a few minutes of vacuum degassing will remove about 60-70% of the dissolved gas (pg. 3 last para.).
Therefore, regarding claims 1, 63 and 65, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that the degassed PBS liquid of Choi, which was degassed for 30 minutes in a vacuum chamber, would contain about 60-70% of the dissolved gas of the dissolved gas content, which would be 30-40% of dissolved gas content compared to a non-degassed liquid, and lies within the claimed ranges of “80% or less” (instant claim 1) and “50% or less” (instant claim 63) and is very close to the claimed range of “20% or less” (instant claim 65) of dissolved gas content compared to a non-degassed liquid.
Regarding claims 1 and 63, 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.
Regarding claim 65, MPEP 2144.05(I) states “a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).” Therefore, in the instant case, the taught range of 30-40% of dissolved gas content of Choi in view of Dolan makes obvious the instantly claimed range of 20% or less because the value of 30% of dissolved gas is so close to the claimed 20% that one of ordinary skill would expect them to have the same properties.
Additionally, regarding claims 1, 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 dissolved gas concentration in the method as suggested by Choi in view of Dolan.
Regarding claims 4-6 and 8, further to the discussion of claim 1 above, Choi teaches the isolated organ portion is a portion of a liver (liver samples) (instant claim 8) and is from a pig (“Porcine liver samples” pg. 2001 col. 2 Materials and Methods) (instant claim 6), which is a mammal (instant claim 4) and is a non-human mammal (instant claim 5).
Regarding claim 9, further to the discussion of claim 1 above, Choi teaches the contacting comprises (iv) submerging the isolated organ or portion thereof in the liquid (pg. 2001 col. 2 Materials and Methods).
Regarding claim 21, further to the discussion of claim 1 above, it is noted that instant claims are directed to only “reduced” residual DNA, 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 and would obviously be met by the combination above of Choi in view of Dolan.
Regarding claim 40, further to the discussion of claim 1 above, Choi teaches washing the isolated organ portion with a wash media prior to the contacting (“immediately placed in phosphate buffer saline … and were stored at 4°C” pg. 2001 col. 2 Materials and Methods).
Hence, the claimed invention as a whole was prima facie obvious.
Conclusion
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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