Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Feb. 11, 2026 has been entered.
Claim Status
Claims 3-5, 8-11 and 13 are currently pending in this application.
Disclosure Objections: specification
Content of Specification, should include: (i) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S): See MPEP § 608.01(f). A reference to and brief description of the drawing(s) as set forth in 37 CFR 1.74.
The specification is objected to because the Brief Description of the Drawings does not contain a description of each figure individually for Figures 19-22, which are instead described collectively despite involving different data sets (e.g., subject numbers and timing).
Claim Objection
Claims 3-5, 8-11 and 13 are objected to because of the following informalities:
Applicant should correct the numbering of the claim set to comply with MPEP §608.01(m) requiring all dependent claims follow after all claims from which it depends and be grouped together with the claim or claims to which they refer to the extent practicable. Appropriate correction is required.
Dependent claim 3 recites the fourth fluid is circulating under a circulation pressure however the claim from which it depends, claim 13, only mentions a fluid under pressure regarding the third fluid. The claim set would be clearer if claim 13 is rewritten to state the fourth fluid is under pressure in the second restoration step using language aligned with the language of the first restoration step, or alternatively, how “circulating” in the second restoration step is achieved without being under a circulation pressure. Appropriate correction is required.
Status of previous rejections
The previous nonstatutory double patenting rejection based on copending application US 17/442922 is withdrawn in view of the terminal disclaimer filed 2/11/26.
Claim Interpretation
The terms “harvested” and “retrieving” are interpreted as meaning removed from the donor, i.e., an extracted or ex vivo lung, and thus, the claims are directed to methods of “recovering” an ex vivo kidney comprising first and second restoration steps.
Claim 13 is interpreted without limitation to the kidney temperature except that the temperature of the kidney must permit circulation of an exogenous fluid as recited in the claims, i.e., a third and fourth fluids between respectively 5-25 °C and 28-37 °C at least as the fluid enters the kidney for circulation. It is noted that although claim 13 recites “providing lys-plasminogen to the kidney” and “providing a tissue plasminogen activator (tPA)” to the kidney, neither claim requires “circulating” of either the first or second fluids through the kidney, such as under pressure and/or via perfusion/reperfusion, as is required for the third and fourth fluids.
Claim Rejections - 35 USC § 112(a) - Written Description
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 3-5, 8-11, and 13 are rejected 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, and 35 U.S.C. 112(b) for indefiniteness. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of. In view of the specification, the claims are directed to a method of evaluating a harvested kidney ex vivo for transplantation via a method comprising (1) contacting the kidney with tissue plasminogen activator (tPA) and lys-plasminogen; (2) a first restoring step comprising circulating through the kidney a fluid under pressure and comprising albumin, electrolytes, and a coagulation inhibitor, wherein the fluid has a temperature between 5-25 °C; and (3) a second restoring step comprising circulating through the kidney a fluid comprising red blood cells, albumin, electrolytes, and a coagulation inhibitor, wherein the fluid has a temperature between 28-37 °C.
The claims are broad in that the temperature of the kidney is unlimited, the temperature of the first fluid and optional second fluid is unlimited, the term “albumin” encompasses any albumin, the term “electrolytes” encompasses any plurality of electrolytes, and the term “red blood cells” encompasses any red blood cells (e.g., an interspecies mixture thereof).
The claims are also broad in that the kidney may always be unsuitable for transplantation based on the evaluating step, and, thus, the claims encompass methods producing unusable kidneys despite performing the recovering and restoration steps as recited. This means the claimed method possessed may solely be a method of confirming unusable harvested kidneys retrieved more than four hours after circulation arrest (e.g., completely inviable kidneys) despite the point of novelty is performing tPA and lys-plasminogen administration step(s) to the kidney (e.g., wherein the conditions are irrelevant because the kidney is already inviable, diseased or the donor is too old). Further, the claims are broad in that although the evaluating can be performed on any kidney (e.g., from any species, blood type, or age), the designation of the transplantation recipient could determine suitability, e.g., no mouse kidney would be deemed suitable for a human recipient regardless of any recovering method steps.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described. The instant specification is silent as to any formal definition for (1) tissue plasminogen activator (tPA), (2) “albumin,” (3) “electrolyte,” or (4) “red blood cells,” so these terms in the claims take their ordinary meanings to a person of ordinary skill in the art at the filing date under a broadest reasonable interpretation.
Tissue plasminogen activator (tPA)
The prior art teaches tPA (tissue-type plasminogen activator) is a naturally occurring protein of vertebrates of which there are over 50,000 different species. There is no instant description of the source of tPA nor any representative species thereof beyond human (alteplase) or possibly any streptokinase, urokinase, reteplase and tenecteplase (Example 10). Without evidence of substitutability across the entire genus (e.g., a nexus described in the instant application or known in the prior art), it cannot be assumed that all tPA’s are predictably interchangeable, such as regarding any species of lung.
Albumin
The art teaches serum albumin is a protein family making up the predominant soluble protein in the blood of most vertebrate species (such as bony fish, birds, and some reptiles) and functioning passively to provide colloidal osmotic pressure and actively as fatty acid/lipophilic hormone carriers and antioxidants (Belinskaia et al., J Evol Biochem Physiol 57: 1419-48 (2021) at abstract, pg. 1420, pg. 1421, left col., last para., to right col., last para.). Albumins can be characterized as a predominant blood plasma protein of a size of about 60-70 kDa protein capable of binding palmitate and having sequence homology to, e.g., an ancestral albumin and within conserved albumin domains to albumins of extant primates (id.). Within the albumin protein family, the albumins of some species are quite divergent in structure and function, e.g., the albumin of birds is uniquely devoid of lysine residues compared to mammalian albumin while the albumin of lampreys is 2.5-fold larger than mammalian albumin.
There is no instant description of the albumin or any representative species thereof. Without evidence of substitutability across the entire genus (e.g., a nexus described in the instant application or known in the prior art), it cannot be assumed that all albumins of the vertebrate albumin family are predictably interchangeable, such as regarding birds and primitive bony fish.
Electrolytes
The art teaches an electrolyte is any substance that can conduct electricity through the movement of ions, as oppose to electrons (en.wikipedia.org/wiki/Electrolyte, last visited April 8, 2026). Thus, electrolyte encompasses virtually any soluble salt dissolved in aqueous solvent as well as biomolecules such as polynucleotides and polypeptides. With regard to organ preservation ex vivo, the common electrolytes are sodium (Na), potassium (K), chloride (Cl), calcium (Ca), and magnesium (Mg) (en.wikipedia.org/wiki/Mineral_(nutrient), last visited April 8, 2026). However the instant claim limitations of any “electrolytes” can be met by two or more of any of the above, including wherein one of the electrolytes is the requisite albumin, a negatively-charged polypeptide depending on the other components present in the solution. The term “electrolyte” encompasses trace minerals, e.g., known to be in human blood, such as manganese, silicon, nickel, and vanadium (Mehri, A., Int J Prev Med. 11: 2 (2020) at Table 2).
The instant application describes methods comprising circulating through the kidney fluids comprising electrolytes at physiological concentrations, such as wherein the fluid is isotonic or hyperoncotic (pg. 3, lines 11-13; pg. 9, lines 7 and 17). Representative species provided in the description include Na, K, Mg, and Ca, such as obtained by dissolving inorganic salts like CaCl2 MgSO4, KH2PO4, KCl, NaHCO3, NaCl, Na2HPO4, and/or HCl. For example, embodiments of the lys-plasminogen fluid, circulation fluid, perfusion fluid, preservation fluid, and/or red blood cell fluid may contain any or none of the electrolytes listed in instant Table A (pg. 16, note concentrations can be zero). Working examples (Examples 9-16) describe first and second fluid embodiments comprising specific electrolytes (Tables H or I), and third and fourth fluid embodiments comprising specific electrolytes (Tables H, J, or K). Thus, the choice and concentration of the electrolytes is left completely to the discretion of the ordinary artisan based on her knowledge and skill in view of these limited representative species.
Red Blood Cells
Red blood cells can be sourced from almost any vertebrate. The instant description does not disclose a single representative species or source, although in the working examples the transplant recipient is a pig, which may imply a suitable source(s) to the skilled artisan (Examples 9-16, FIG. 13-15 and 19-24).
“Suitability” of transplantation
The description does not define “suitability” of transplantation, or any method of evaluating such, but does note that kidneys experiencing more than two hours of “warm” ischemia can be considered unsuitable for transplantation as can kidneys “normally” harvested more than one hour after donor cardiac arrest (instant pg. 1, lines 16-17 and 28-29). The specification describes evaluation parameters may include visual appearance (lack of large dark areas), vascular resistance, urine production and creatine, such as before or after transplantation (see Fig. 13-15 and 19-24). The prior art teaches numerous parameters and criteria relevant for making decisions about prospects for transplantation, such as donor medical history/age, malignancy, observable damage (macroscopic/histological), ex vivo perfusion quality indicators (e.g. failed in situ perfusion, mean pressure/vascular resistance and urine processing), or any absolute contraindication to transplantation (Hosgood at pg. 1434-1435, Tables 1-2). Thus, suitability could exclude any diseased kidney, any kidney from a virally infected or elder donor, any kidney from a donor with kidney disease, any kidney any human kidney experiencing more than two hours of “warm” ischemia as well as all human kidneys harvested more than one hour after donor cardiac arrest (instant pg. 1, lines 16-17 and 28-29), and yet performing the claimed method on all of these kidneys falls within the scope of claim 13.
The specification fails to provide a single working example wherein a transplant suitable kidney is produced by the claimed methods when the kidney is not porcine or the method lacks keeping the kidney at temperature between 15-32 °C during the first and second restoration steps, lacks a first fluid as in Table H and comprising antithrombin III (ATIII), lacks a third fluid as in Table J or K with albumin at 72 g/L, lacks a fourth fluid as in Table K with albumin at 57 g/L and comprising ATIII, abciximab and argatroban (see instant Examples 2-16). Thus, no working example is described for coagulation inhibitors other than: ATIII, abciximab and/or argatroban or albumin concentrations over 72 g/L. Thus, there is unpredictability across the scopes of any temperature and any electrolytes without further empirical data in view of the breadth of the prior art. Furthermore, the source/type of the tPA, albumin, and red blood cells in the working examples are not disclosed, except for the tPA being human tPA in some examples (alteplas) (Examples 2 and 9-10).
The skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of the full scope of the broadly claimed methods. The dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of independent claim 13. Adequate written description of a method requires more than statements of broad steps recited at a high level of generality yet purporting to achieve a suitable kidney for transplantation harvested more than four hours after circulation arrest (as implied by the claims at least for some situations or definitions of “suitability of transplantation”).
Furthermore, the claims 3-5, 8-11, and 13 are indefinite for comprising too many broad variables simultaneously (MPEP §2173.05(b)), e.g., depending on the “suitability” of which type of transplantation combined with any kidney type (e.g., from any biological species), any tPA, any albumin, any electrolytes, unlimited kidney temperature, and any red blood cell source concomitantly selected as discussed above. The dependent claims are indefinite because they do not correct the primary deficiencies of claim 13.
35 USC § 112(a) – Scope of Enablement
Claims 3-5, 8-11, and 13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while enabling wherein the kidney, tPA, lys-plasminogen are all mammalian, the kidney is initially at a temperature of 15-37 °C during the providing steps and start of the first restoration step and at least 28 °C by the end of the second restoration step, the first fluid is under pressure and at a temperature of at least 15-37 °C; does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to produce a suitable kidney for transplantation harvested more than four hours after circulation arrest for non-mammalian elements (kidneys, tPA, or lys-plasminogen) and any kidney temperature (e.g., any circulating duration).
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue.' Not 'experimentation;" (Wands, 8 USPQ2d 104). 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 weighting many factual considerations." (Wands, 8 USPQ2d 1404).
The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature and Breadth of the invention:
The claims are directed to methods of evaluating a harvested kidney ex vivo for suitability for transplantation via a method comprising (1) contacting the kidney with a fluid(s) comprising tissue plasminogen activator (tPA) and/or lys-plasminogen; (2) a first restoring step comprising circulating through the kidney a fluid under pressure and comprising albumin, electrolytes, and a coagulation inhibitor, wherein the fluid has a temperature between 5-25 °C; and (3) a second restoring step comprising circulating through the kidney a fluid comprising red blood cells, albumin, electrolytes, and a coagulation inhibitor, wherein the fluid has a temperature between 28-37 °C. Although it is implied that this method can produce an ex vivo kidney suitable for at least one type of transplantation despite being harvested more than four hours after circulation arrest, the method steps are only recited at a high level of generality regarding multiple variables: e.g., temperatures, durations, and species of kidney, lys-plasminogen, and tPA. Furthermore, the invention cannot be simply evaluating a kidney ex vivo for transplantation and finding it is not suitable as was performed previously in the prior art, but rather the invention should be directed to successfully recovering a harvested kidney by providing exposure to the lys-plasminogen and tPA to, at least in some cases, produce an ex vivo kidney that is actual suitable for use in some type of transplantation (i.e., wherein the evaluation prediction matches reality), such as limited by a maximum time after circulation arrest (e.g., 5 hours) as in the working examples.
The state of the art:
The prior art teaches evaluating ex vivo kidney criteria to produce an overall assessment score (Table 1) useful in assessing kidney quality and decisions regarding suitability for transplantation (Hosgood et al. (2015) at Abstract; pg. 1434, right col., last para.; pg. 1434, left col., para. 1-2), including merely to accomplish evaluating all kidneys retrieved after four hours from donor circulation arrest as unsuitable for transplantation. However the prior art does not teach the full scope of evaluating any non-mammalian lung using perfusion to assess suitability for transplantation, administering any tissue plasminogen activator (tPA), perfusates for lungs having any albumin, electrolytes and/or red blood cells and then successfully transplanting the lung into any recipient.
The amount of direction and guidance and working examples provided by Applicant:
The disclosure provided by the applicant, in view of prior art, must encompass a wide area of knowledge to a reasonably comprehensive extent to enable a kidney suitable for transplantation is produced by a method of exposing a kidney harvested more than four after circulation arrest by restoring/recovering it via ex vivo exposure to both lys-plasminogen and tPA, especially wherein the maximum time after circulation arrest is unlimited. In other words, each of these aspects must be shown to a reasonable extent so that one of the ordinary skills in the art would be able to practice the invention without any undue burden being on such Artisan.
The instant application shows working examples only with pig donors and recipients (i.e., porcine kidneys) wherein the kidney temperature is between 15-32 °C during the first and second restoration steps (Examples 2-16). Thus, this evidence is only found in working embodiments and as suggested by the prior art for other related cell types (e.g., mammalian tissues and factors). Furthermore, the source/type of the tPA, albumin, and red blood cells in the working examples are not disclosed, except for tPA being human tPA in some working examples (alteplas).
Thus, the scope of unlimited kidney, lys-plasminogen, tPA, and kidney temperatures by the claims is merely prophetic. Extensive experimentation would be required to adjust all these variables at once to adapt the claimed method to each type of non-mammalian vertebrate, and may never be successful at producing a kidney suitable for transplantation in any situation. Given the lack of working examples, the limited guidance provided in the specification, the lack of guidance in the prior art, and the broad scope of the claims with regard to any temperatures or circulating durations, and species of kidney, lys-plasminogen, and tPA; undue experimentation would have been required for one skilled in the art to perform the full scope of the claimed invention as presently recited in the claims.
Response to Remarks
Applicant’s remarks of Feb. 11, 2026 (pg. 4, “Substance of the Interview”) appear to incorrectly state the Office expressed any indication that the present claim amendments would place the claims in condition for allowance, such as during an interview or other communication. To clarify the record, at most the Examiner may have indicated the present claim amendments would possibly overcome previous rejections of record; however, as noted herein, numerous outstanding issues remain.
As the instant Examiner has no record of any such communication (or even an interview occurred on or around Feb. 10, 2026 with Applicant or their representative), Applicant and their representatives are reminded of MPEP 410 and 37 C.F.R. § 11.18(b) stating that signed correspondence with the Office certifies that statements made therein of the party’s own knowledge are true, all statements made therein on information and belief are believed to be true, and all statements made therein are made with the knowledge that whoever, in any matter within the jurisdiction of the Office, knowingly and willfully falsifies, conceals, or covers up by any trick, scheme, or device a material fact, or knowingly and willfully makes any false, fictitious, or fraudulent statements or representations, or knowingly and willfully makes or uses any false writing or document knowing the same to contain any false, fictitious, or fraudulent statement or entry, may be subject to disciplinary action and/or criminal penalties (e.g., as set forth under 18 U.S.C. 1001).
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 3-5, 8-11 and 13 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 13 recites the term “suitability of transplantation” regarding the result of an evaluating step. This term is neither defined by the claims nor the instant specification and may be considered both subjective and overly broad. A claim may be rendered indefinite by reference to an object that is variable (see MPEP §2173.05(b)). Here, the determination of the scope of “suitability of transplantation” depends on unrecited variables, such as the intended recipient, the donor species, and donor health; and thus claim 13 is indefinite for use of this term. The suitability for a specific type of transplantation (matched recipient) coupled with a clear standard criterion/criteria, baseline and/or boundary between what is suitable and what is not could inform the skilled artisan of the metes and bounds of this term as used in the claim to limit the evaluating step. Claims 3-5 and 8-11 are included in this rejection for being dependent on indefinite claim 13.
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.
Claims 3-5 and 8-11 are 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.
Each of claims 3-5 and 8-11 have been amended to recite dependency upon later presented independent claim 13. Thus, the order of the claims is neither in accordance with MPEP §608.01(m) nor compliance with 35 U.S.C. 112(d) - a claim in dependent form shall contain a reference to a claim previously set forth. It would be remedial to amend the claims such that current claim 13 is set forth prior to any claim depending therefrom, either directly or indirectly.
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.
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 4-5 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Hosgood (Hosgood et al., Br J Surg 102: 1433-40 (2015)) in view of Scalea (Scalea et al., Am J Transplant 17: 191-200 (2016)), Eibl (US 5,520,912 A), Kaths (Kaths et al., J Vis Exp 101: e52909 (2015), and Steen (US20140007961A1).
The claims are interpreted as explained in a previous section. In addition, the preamble phrase “recovering a kidney” is considered to imply nothing more than the method improves the chance of producing a viable kidney from the harvested kidney, and thus, the method of claim 1 is performed under conditions not contrary to providing a viable kidney. Furthermore, the “evaluating” step of claim 1 does not imply any limitation not recited in the claim, such as an implied structural or functional characteristic(s) of the recovered kidney, as the kidney need not be evaluated as suitable for transplantation.
Hosgood teaches methods comprising retrieving/harvesting a kidney from a cardiac arrest mammalian donor after circulation arrest (i.e., DCD kidney), initially storing the kidney on ice, perfusing the harvested kidney ex vivo (EVNP) and evaluating the kidney for suitability of transplantation wherein the methods comprise a restoration step (pg. 1433, right col., last para., to pg. 1434, left col., 3rd para.) of circulating through the kidney a fluid comprising physiological electrolytes (supplemented Ringer’s solution) and oxygenated mammalian red blood cells (RBC) at near human body temperature (e.g., ~36 °C or normothermic) under pressure (e.g., 70-75 mmHg) for 1 hour, such as prior to transplantation to increase oxygenation of kidney tissues, reduce ischemic reperfusion injury, and improve graft function (pg. 1434, left col., 4th para., to right col., last para.; pg. 1435, left col., 4th para.; Abstract). Hosgood teaches using the evaluating step criteria to produce an overall assessment score (Table 1) useful in assessing kidney quality and decisions regarding suitability for transplantation (e.g., risk assessment) (Abstract; pg. 1434, right col., last para.; pg. 1434, left col., para. 1-2). Hosgood teaches such ex vivo kidneys may optionally be subjected to hypothermic perfusion (HMP), e.g., at 5-8 °C (pg. 1434, left col., right para.).
Regarding claim 13, while Hosgood teaches the evaluating step as well as a steps similar to the retrieving and “second restoration step,” Hosgood does not teach (1) retrieving the kidney at least four hours after circulation arrest of the donor; (2) providing to the kidney any fluid(s) specifically comprising lys-plasminogen and/or a tissue plasminogen activator (tPA); (3) a first restoration step of circulating through the kidney a fluid (at a temperature between 5-25°C under pressure) comprising 50-120 g/L of an albumin, electrolytes, and a coagulation inhibitor; or (4) wherein the second restoration step comprises a perfusate fluid specifically comprising 50-120 g/L of an albumin and a coagulation inhibitor.
However Scalea teaches harvesting kidneys after circulatory death (DCD) at 3-4 to 12 hours after treatment withdraw (TTD) could expand the kidney donor pool by 12.5-50%, which occurs after circulation arrest of the kidney and agonal time, e.g., removal of life support machine and induced coma, does not affect outcomes of kidney transplantation based on timing (pg. 199, left col., last para., to right col., 1st para.; pg. 191, 1st para.; Abstract; Fig. 4, 6). Scalea teaches evaluating donor kidney function after transplantation by criteria of medical needs for hemodialysis as a proxy for inferior renal function, such as time to next hemodialysis treatment of the recipient (i.e., delayed graft function (DGF)) (pg. 191, 1st para.; 192, left col., 2nd para.).
Kaths teaches a traditional method of maintaining a harvested kidney (hypothermic machine perfusion) comprises circulating through the organ a hyperoncotic fluid (STEEN solution) comprising albumin, physiological electrolytes, and anticoagulant (heparin) to keep oncotic pressure and osmolarity within a physiological range (pg. 12, 4th para.; pg. 3-4, Preparation of Perfusion Solution). As evidenced by Steen, a STEEN solution may comprise albumin at 50 g/L (5%) with the solution used at a temperature between 5°C and 25°C, e.g., 10° C or less (hypothermic) ([0103]; [0106]).
Eibl teaches both lys-plasminogen and tissue plasminogen activator (t-PA) treatments provide protective effects to organs damaged by ischemia and reperfusion (col. 6, lines 49-58; col. 8, lines 4-11), and lys-plasminogen treatment is useful in the preservation of organs for transplant by minimizing ischemic damage (col. 7, 60-63) and for treating damage caused by reperfusion and/or ischemia (Abstract; col. 4, line 64, to col. 5, line 5). Eibl teaches administering both lys-plasminogen along with t-PA may improve vascular flow via fibrinolysis, e.g., of blood clots (col. 8, lines 4-11; col. 4, lines 20-56), and for use in methods of improving microcirculation (col. 5, lines 1-2).
It would have been prima facie obvious to one of ordinary skill in the art at the time of filing to apply the method of Hosgood to a DCD donor kidney retrieved at least four hours after circulation arrest in view of Scalea to test expanding the available kidney donor pool. One of ordinary skill in the art would be motivated to widen the supply of donor kidneys to better meet the medical demand in view of Hosgood teaching a significant number of available donor kidneys are discarded that may pass testing for translatability (Abstract) and teaching screening by pretransplant ex vivo perfusion assessment scoring assay kidneys already deemed to be discarded (pg. 1433, to pg. 1434, left col., 2nd para.). Furthermore, one of ordinary skill in the art would be motivated to use an ex vivo kidney evaluating step taught by Hosgood to decide (or aid in the decision process) whether each individual DCD kidney could be made suitable for transplantation, such as due to additional interventions.
Moreover, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to include in the procedure of Hosgood before its restoration step a conventional EVP step of circulating through the kidney a hypothermic fluid comprising albumin 50 g/L, physiological electrolytes, and an anticoagulant as taught by Kaths as well as to use the same base perfusate solution during the Hosgood (second) restoration step, i.e., STEEN solution comprising 50 g/L albumin, physiological electrolytes, and anticoagulant. One of ordinary skill in the art would be motivated to obtain donated kidneys, many of which are subjected to this step already, or to perform this step to maintain oncotic pressure and osmolarity within a physiological range upon first recovery and/or reperfusion to maintain kidney health as taught by Kaths and as a step toward temperature increase from cold ischemia (e.g., without perfusion) to normothermic perfusion as taught by Hosgood.
Further, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to modify the method of Hosgood to comprise providing to the ex vivo kidney a hyperoncotic fluid comprising both lys-plasminogen and t-PA simultaneously as taught by Eibl. One of ordinary skill in the art would be motivated to minimize or treat ischemic damage and minimize or reduce blood clotting to increase kidney functionality and transplantation suitability to try an expand the donor kidney supply. Finally, one of ordinary skill in the art would be motivated to use the evaluating step of the ex vivo perfusion method of Hosgood after the final restoring step to decide whether an individual kidney was suitable for transplantation using kidney quality criteria (e.g., macro-appearance, blood flow, and urine output (Table 1)).
Regarding claims 4-5, although Hosgood teaches hypothermic storage of the restored kidney after EVNP with hypothermic EVP (HMP) and/or storage on ice (pg. 1434, left col., 3rd para.; pg. 1435, 4th para.), Hosgood does not teach the preservation fluid is circulated through the kidney at a pressure below 30 mmHg for at least one hour during this low temperature storage.
However Steen teaches storing an organ ex vivo in a perfusion machine at a hypothermic temperature between 4-16°C (10° C or less) while circulating a preservation fluid (STEEN solution) through the organ at a pressure below 30 mmHg (at least 15 mmHg) for a duration of 4 or 6 hours on battery power for transport by airplane to any medical site within Europe ([0103]; [0106]-[0107]; [0007]). Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to perform the method of Hosgood, as modified by Eibl, Kaths, and Scalea, wherein after the final restoration step the kidney is stored and transported via hypothermic machine perfusion with STEEN solution at 15 mmHg for 4-6 hours for delivery of the restored kidney to a transplant recipient at a distant hospital.
Claims 4-5, 8, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Hosgood in view of Scalea, Eibl, Kaths, and Steen as applied above, and further in view of Soule (Soule et al., Transplantation 78(2): 658 (2004)).
Regarding claim 8, the combination of Hosgood, Scalea, Eibl, and Steen does not teach wherein at least one of the perfusates comprises one of a direct thrombin inhibitor, protein C, protein S, or platelet inhibitor.
However Soule teaches substituting heparin with the direct thrombin inhibitor argatroban for use with subjects allergic to heparin (abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time of filing to perform the procedure of Hosgood as modified by Scalea, Eibl, Kaths, and Steen wherein the heparin anticoagulant taught by Kaths is substituted with argatroban as taught by Soule during the Hosgood (second) restoration step, i.e., STEEN solution comprising 50 g/L albumin, physiological electrolytes, and anticoagulant. One of ordinary skill in the art would be so motivated for preparing an ex vivo kidney for transplantation into those recipients having heparin allergies, as this constitutes a prior art use for a known prior art substitute.
Claims 4-5, 9, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Hosgood in view of Scalea, Eibl, Kaths, and Steen as applied above, and further in view of Roman (Roman et al., Transplantation 96: 509-18 (2013)).
Regarding claim 9, the combination of Hosgood, Scalea, Eibl, Kaths, and Steen does not teach either the restoring step perfusates (i.e., third or fourth fluids) is passed through a leucocyte-filter.
However Roman teaches filtering organ perfusion fluids using leukocyte filters (leukocyte depletion filter) is beneficial in reducing alloimmune reactivity by removing donor-derived immune cells, e.g., by reducing/preventing the presence of monocytes, inflammatory macrophages and/or dendritic cells in the organ that can release proinflammatory cytokines and promote organ rejection (pg. 515, left col., 2nd para.; pg. 513, right col., para. 4).
It would have been prima facie obvious to one of ordinary skill in the art at the time of filing to include in the procedure of Hosgood as modified by Scalea, Eibl, Kaths, and Steen a leukocyte-depletion filter in any perfusion step to filter any of the perfusates, especially the penultimate solution, to remove potentially dangerous donor-derived immune cells prior to transplanting the kidney into a recipient. One of ordinary skill in the art with the goal of preparing the kidney for medical transplantation use would be motivated by safety reasons to do so as taught by Roman.
Claims 4-5, 10-11, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Hosgood in view of Scalea, Eibl, Kaths, and Steen as applied above, and further in view of Brady (US20020197252A1).
Regarding claims 10-11, the combination of Hosgood, Scalea, Eibl, Kaths, and Steen does not teach either restoring step perfusates (i.e., third or fourth fluids) is passed through a cytokine adsorber or endotoxin adsorber.
However Brady teaches methods of removing unwanted factors from a body fluid or organ for transplantation by selective adsorption ([0035]-[0036]; [0031]), including cytokines and LPS endotoxin ([0037]; FIG. 15; [0179]-[0181]; FIG. 13), e.g., by exposure of a circulating fluid to a cytokine adsorption medium ([0038]) or endotoxin adsorption medium ([0179]). Brady teaches it is desirable to remove excessive inflammatory cytokines and inflammatory endotoxin, which can cause significant tissue injury and even death, such as via septic shock during allotransplantation ([0005]; [0008]-[0010]; [0021]).
It would have been prima facie obvious to one of ordinary skill in the art at the time of filing to include in the procedure of Hosgood, as modified by Scalea, Eibl, Kaths, and Steen, contacting the Steen albumin solution and/or RBC solution to a cytokine adsorber or endotoxin adsorber to remove potentially dangerous inflammatory factors. One of ordinary skill in the art with the goal of preparing the kidney for medical transplantation use would be motivated by safety reasons to do so as taught by Brady to avoid detrimental inflammatory responses.
Thus, the claimed invention as a whole is prima facie obvious to one of ordinary skill in the art before the earliest effective time of filing in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments of Feb. 11, 2026 (pg. 5 of 7) are fully considered but not found to be persuasive for the reasons set forth above as claim 13 alone does not overcome obviousness in view of the prior art of record.
Conclusion
No claim is allowed.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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