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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 Jan. 5, 2026 has been entered.
Claim Status
Claims 69, 543-544, 546-551, 556-559, and 568-575 are currently pending in this application. All arguments have been fully considered.
Benefit of Priority Claim
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. US 62/863,034, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for all the instant claims because US 62/863,034 supports the claimed method only wherein the mitochondria are porcine and wherein the mitochondria storage temperature is no lower than -80°C. Therefore the earliest effective filing date of the claims is June 17, 2020.
Disclose Objections - Specification
The disclosure is objected to because of the following informalities:
Although the use of trademarks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The use in the specification of the terms “STEEN,” “Perfadex,” “Pluronic,” Gelfoam,” “CryoStor,” “TeSR,” “Eppendorf,” “Seahorse,” Seahorse XF, “Seahorse Bioscience,” “Sartorius,” “Nova Biomedical,” “SYTOX,” “SAGM,” “BulletKit,” and “Lonza,” each of which is a trademark used in commerce, has been noted in this application. The marks should be accompanied by the generic terminology; furthermore these terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Appropriate correction at numerous instances in the specification is required because the proprietary nature of trademarks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 573 is objected to because of the following informalities:
Claim 573 recites the phrase “reduces apoptotic signaling pathway,” which would be clearer if rewritten as “reduces an apoptosis signaling pathway,” “reduces one or more apoptosis signaling pathways,” or “reduces an apoptotic signaling pathway” in better grammatical alignment with related wordings in the claim set.
Claim Interpretation
In claim 69, the term “cold” ischemia under a broadest reasonable interpretation encompasses any “cold” temperature relative to a viable lung at its respective physiological temperature, such as any subnormothermic temperature, e.g., less than about 14-29 °C for most mammals, as this term is not defined by the instant application. In the claims, the duration of “cold” ischemia is interpreted as the time from which an ischemic lung is initially brought to the subnormothermic temperature and kept at or lower than this temperature without interruption, i.e., exposing the ex vivo lung to continuous “cold” ischemia for the recited duration.
In the claims, the term “ex vivo lung perfusion” is interpreted as meaning any perfusion of a lung in an ex vivo setting as this term is neither limited in the claims nor defined in the instant specification.
Note, the order of performing process steps is not ordinarily construed to be any specific order or as non-concomitant unless specified by the claim or when the claim language, as a matter of logic or grammar, requires that the steps be performed in a specific order or when the specification directly or implicitly requires an order of steps. For instant in claim 69, the phrase “on the ex vivo lung exposed to the at least 12 hours of cold ischemia” is interpreted as requiring performing the exposing step for at least 12 hours before performing the perfusion step.
In claims 556-558, the time period demarking “exposed to the cold ischemia” is interpreted as encompassing any timepoint within the cold ischemia of at least 12 hours. Thusly, 24 hours after “exposed to the cold ischemia” encompasses 24 hours after commencement of the cold ischemia (i.e., 12 hours after ending a 12 hour cold ischemia) up to as long as 24 hours from the ending of the cold ischemia (i.e., 36 hours from the start of a 12 hour cold ischemia).
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 69, 543-544, 546-551, 556-559, and 568-575 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. 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.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicant’s effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
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, claim 69 is directed to a method comprising (i) exposing an ex vivo lung to at least 12 hours of cold ischemia and then (ii) perfusing the lung ex vivo and (iii) delivering isolated mitochondria to the lung ex vivo.
The claims are broad in that the claims encompass any lung, any mitochondria matched with the lung, any perfusion solution, and any perfusion conditions, and yet, very specifically recited effects are predicted to occur across this scope. Additionally, claims 548, 551 and 570-573, introduce more specifically recited effects.
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.
Lung Genus
The instant specification provides a description of only a limited number of species: porcine or human mitochondria administered to porcine or human lungs ([0200]). However the term lung in the claims encompasses any lung, of which there are over 50,000 different vertebrate species having lungs (www.wikidoc.org/index.php/Vertebrate, last visited April 16, 2026), such as species having small and fragile lungs. Furthermore, some species of lung are from cold-blooded vertebrates (ectotherms), most of which are poikilotherms whose body temperatures, and thus their lung physiological temperature ranges, vary with environment conditions, such as reptiles and lungfish . There is not a nexus with regard to the instant invention between the two representative species (pigs and human) and the scope of all vertebrates with lungs.
Mitochondria Genus
The instant specification provides a description of only a limited number of donor species for obtaining mitochondria, all mammalian: primates, pigs, sheep, canines, rabbits, mice, and rats ([0008]). However there are over a million different biological species having mitochondria (eol.org/pages/2908256, last visited April 16, 2026). There is not a sufficient nexus with regard to the instant invention between the limited representative mammalian species described and the scope of all donor species having mitochondria (e.g., diverse plants, fungi, algae, fish, etc.).
Perfusion Conditions
The instant specification provides a description of only a single perfusion condition producing the effects recited in claim 69. However, claim 69 encompass wherein the isolated mitochondria are administered via injection into the ex vivo lung perfusion (EVLP) input line, a pulmonary artery, the lung tissue directly ([0210]) as well as any other method known in the prior art.
Claim 69 recites the functional limitations of wherein the delivering produces one or all of the following effects in the lung: (1) reduces expression of a reactive oxygen species (ROS)-induced DNA activation maker, (2) increases expression of one or more gap junction markers, (3) reduces one or more inflammatory signaling pathways and (4) reduces production of one or more inflammatory cytokines in the ex vivo lung.
In claim 69, all the process steps are each recited at a high level of generality yet must ensure the aforementioned four effects occur due to the delivering step. As the limitations listed above (1)-(4) are not all reasonably predicted to occur merely by performing the process steps recited in the claim, one skilled in the art would not find applicant had possession of the claimed invention as currently claimed.
Firstly, the prior art is silent as to any of these effects (1)-(4) expressly resulting from a method comprising an ex vivo lung exposed to 12 hours of cold ischemia or longer that has been delivered exogenous mitochondria exposed to freeze/thaw. Second in the working examples, to yield the recited results (1)-(4), the method used only mammalian mitochondria and mammalian lungs of the same biological species (porcine) and relied on a perfusion step comprising ventilation, restoring physiological temperature (rewarming), a deoxygenated and physiologically buffered perfusate comprising glucose and maintaining oncotic pressure and physiological ion concentrations (i.e., Steen Solution® or Organ Care System (OCS™)), wherein the mitochondria are administered by perfusion and the total perfusion duration is at least for 5 hours at 37 °C (Example 11, FIG. 40-43). The amount of mitochondria injected into the perfusate appears undisclosed in the working examples. The same is the only example provided for the additional/narrower results recited in claims 544, 547-548, 550-551 and 569-573.
Moreover, Applicant’s own arguments in the record stress this: there is a lack of guidance in the prior art of ex vivo lung perfusion methods for small and fragile lungs, such as for lungs of mice or amphibians (see end of pg. 12 of response filed 1/5/26).
Claim 69 is also broad in that the time of delivering may be at any time during ex vivo perfusion, such as at the end of the 12 hours of cold ischemia and start of ex vivo perfusion or over 36 hours after initial cold ischemia, for example after 4 weeks. However, the working examples only report empirical data for within 25 hours of initiating cold ischemia.
Regarding claims 69, 543-544, 547-551, and 568-573, the delivering must produce one or more specifically recited effects, thus an effective dose/dosage of isolated mitochondria need be delivered to produce the appropriate effect(s) for each claim. However the claims fail to recite any numerical amount of mitochondria delivered and, thus, the recited effects are not predicted to occur over the scope of any claim, unless it is argued that delivering the isolated mitochondria is not responsible for the effect(s).
McCully teaches delivering/injecting 1 x 1010 to 1 x 1014 or more mitochondria to a large organ, such as an ex vivo lung, in a single dose or cumulative doses (pg. 27, lines 7-30). Although the instant specification shows the recited effects occurring as claimed for a cold ischemia duration of 20 hours, the amount of mitochondria delivered during perfusion is not disclosed. Thus, a nexus has not been established in the record between any of the recited effects occurring and any specific/minimum amount of mitochondria delivered. This empirical data does however establish all the effects recited in claims 69, 543-544, 546-551, and 568-573 can occur by a single method encompassed by claim 69, at least in some situations.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a given mitochondrial dosage to achieve less than all the effects recited in claim 69. Further, the specification fails to describe possession of a mitochondria dose/dosage choice, or how to arrive at such, that achieves less than all the effects recited in claim 69 or that predictably satisfies claim 69 without simultaneously and inherently satisfying all the limitations of claims 543-544, 546-551, and 568-573.
Claims 69, 544, 547, 549, and 568-569 recites the required results of:
(1) reduced expression of reactive oxygen species (ROS)-induced DNA activation maker (e.g., 8-hydroxy-2'-deoxyguanosine),
(2) increased expression of a gap junction marker(s) (e.g., JAM1 or CD31),
(3) reduction in an inflammatory signaling pathway(s) (e.g., an IL-8, Endothelin-1, IL-6, STAT-3, IL-1, mTOR, eNOS, TNFR2, TNFR1, and/or NF-KB signaling pathway), or
(4) reduced production of one or more inflammatory cytokines (e.g., IL-6 or IL-8).
However all the active method steps are recited solely in claim 69 and these steps of (1) storing, (2) exposing, (3) performing ex vivo perfusion, and (4) delivering are each recited at a high level of generality. As the limitations (1-4) listed above are not all reasonably predicted to occur merely by performing the method steps recited in claim 69, one skilled in the art would not find applicant had possession of the full scope of the claimed invention. Furthermore, claims 548, 551, and 570-573 add additional results of:
(5) reduction of an apoptotic signaling pathway, and
(6) reduced pulmonary vascular resistance.
However again all the active method steps are recited solely in claim 69 at a high level of generality. As the limitations (5-6) listed above are not all reasonably predicted to occur merely by performing the method steps recited in the claim, one skilled in the art would not find applicant had possession of the claimed invention. This conclusion is in view of the prior art showing PVR reduces over time during EVLP but in a statistically insignificant manner (Becker et al., Transpl Int. 29: 88-97 (2016) at Fig. 4).
Thus, the written description does not support the full scope of the current claims with regard to the scope of lung (e.g., encompassing mouse lungs), matching mitochondria from any species with lung from any species, and unlimited ex vivo lung perfusing conditions. 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 entire scope of the methods of claims 69, 543-544, 546-551, 556-559, and 568-575.
35 USC § 112(a), Scope of Enablement
Claims 69, 543-544, 546-551, 556-559, and 568-575 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because while enabling the method of claim 69 wherein the lung is of a large mammal, the mitochondria are mammalian, the perfusion step comprises physiological conditions and nutrition over several hours and ventilation/oxygenation/RBCs, and the isolated mitochondria are injected into a perfusion input solution/line; the specification does not enable any person, skilled in the art to which it pertains, or with which it is most nearly connected to, to perform the method recited in claim 69 to predictably produce the effects of: (1) reduces expression of a reactive oxygen species (ROS)-induced DNA activation maker, (2) increases expression of one or more gap junction markers, (3) reduces one or more inflammatory signaling pathways and/or (4) reduces production of one or more inflammatory cytokines across the full scope of claim 69.
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.
Breadth of claims
Claim 69 is directed to a method comprising (i) exposing an ex vivo lung to at least 12 hours of cold ischemia and then (ii) perfusing the lung ex vivo and (iii) delivering isolated mitochondria to the lung ex vivo, such that all of the following effects occur in the lung, at least under some circumstances: (1) reduced expression of a reactive oxygen species (ROS)-induced DNA activation maker (e.g., 8-hydroxy-2'-deoxyguanosine), (2) increased expression of one or more gap junction markers (e.g., JAM1 and CD31), (3) reduced one or more inflammatory signaling pathways (e.g., an IL-8, Endothelin-1, IL-6, STAT-3, IL-1, mTOR, eNOS, TNFR2, TNFR1, and/or NF-KB signaling pathway), and (4) reduced production of one or more inflammatory cytokines (e.g., IL-6 and/or IL-8).
The claims are broad in that the lung maybe from any species, any mitochondria may be matched with the lung, and any perfusion conditions (e.g., any amount of mitochondria) may be used, and yet, very specifically recited effects are predicted to occur across this scope. Additionally, claims 548, 551 and 570-573, introduce more specifically recited effects.
The claims are also broad in that the delivering can be at any time during the ex vivo perfusion step, such as after 12 hours of cold ischemia or after 4 months of cold ischemia and, similarly after 1 second of ex vivo perfusion or 4 weeks of ex vivo perfusion.
The state of the art:
The prior art teaches various methods for organ preservation, assessment, and reconditioning, such as using machine perfusion for marginal donor organs (Jing et al., Acta Pharmacol Sin 39: 845-57 (2018) at abstract, pg. 845; pg. 849, last para., to pg. 850 1st para.; Table 2). Jing teaches a motivation to try to prolong preservation times and that EVLP (ex vivo lung perfusion) specifically has been used to assess donor lung function and improved upon by researching better methods and perfusates, e.g., chemically defined colloids supplemented with erythrocytes or blood substitutes (acellular) (pg. 850-851). EVLP is performed by machine perfusion and can be at hypothermic (HMP), normothermic (NMP), or subnormothermic (SNMP) temperatures (id.).
Jing notes that the perfusate provides nutrition, typically as glucose, and that temperature and temperature changes can alter mitochondria damage and apoptotic signaling as well as nutritional needs (id.). Jing teaches EVLP methods aimed at lung repair/reprogramming, such as by adding therapeutics and prophylaxics to the perfusate, and achieving reductions in edema, apoptosis, and inflammatory markers (pg. 851-852).
The prior art teaches ex vivo lung preservations methods comprising cold ischemia (e.g., 10-24 hours) followed by EVLP using various perfusates (e.g., STEEN® solution, Perfadex®, Celsior®, Custodiol®) for mammalian lungs (e.g., porcine, rabbit, guinea pig, or rat) (Erasmus, ME. Pulmonary surfactant and lung transplantation (1997); Cypel et al., Am J Transplant 9: 2262-9 (2009); Pego-Fernandes et al., Transplant Proc. 42: 444-7 (2010); Becker et al. (2016) at Fig. 4, Hsin et al., J Heart Lung Transplant 35: 130-6 (2016)), such as relying on the EVLP to minimize damage cause by prolonged cold ischemia (Medeiros at Abstract, Fig. 4, pg. 308, right col., 2nd para., to pg. 309, left col., 2nd para.). The prior art teaches EVLP using different temperatures and durations, e.g., hypothermic (< 8 °C) for as much as 6 hours or normothermic (> 35 °C) for about 1-18 hours (id., WO2018/184100A1 at [0177], Examples 6 and 8).
The prior art teaches evaluating lung parameters, including PVR, apoptotic markers, oxidative damage markers, gap junction markers, and inflammation (Cypel et al. (2009) at Fig. 3, 5; Becker et al. (2016) at Fig. 4, Table 1; Hsin et al. (2016) at Fig. 2, 5-6; Tan et al., J Surg Res 245: 273-80 (2019) at Fig. 3-4). For example, Cypel teaches evaluating gap junction marker expression after EVLP of a lung first exposed to 12 hours cold ischemia (i.e., ZO-1) and Becker suggests a reduction in PVR during EVLP of a lung first exposed to 24 hours of cold ischemia in the absence of any exogenous mitochondria administration (Becker et al. (2016) at Fig. 4).
However Medeiros teaches exposing an ex vivo lung to cold ischemia for 10 hours followed by EVLP (ex vivo lung perfusion) without deterioration of tissue and less apoptosis (Abstract, Fig. 4, pg. 308, right col., 2nd para., to pg. 309, left col., 2nd para.), such as to allow for expanding the pool of transplantable lungs beyond previous donor criteria by using the EVLP stage to screen for additional transplantable lungs (e.g., less damaged) from among a marginal by often excluded donor lung pool. Medeiros teaches EVLP can (id.).
However the prior art is silent as to using non-mammalian mitochondria, performing EVLP on a mouse or non-mammal lung (e.g., amphibian), wherein the perfusion step lacks ventilation, or when the perfusate is not deoxygenated and buffered. Regarding claims 544, 547, 550, 569, 571, and 573, the prior art is silent as to any of these additional effects expressly resulting from a method comprising an ex vivo lung exposed to 12-15 hours of cold ischemia or longer: (1) reduced expression of a reactive oxygen species (ROS)-induced DNA activation maker (e.g., 8-hydroxy-2'-deoxyguanosine), (2) increased expression of one or more gap junction markers (e.g., JAM1 and CD31), (3) reduced apoptotic signaling, (4) reduced production of one or more inflammatory cytokines (e.g., IL-6 and/or IL-8), (5) reduced pulmonary vascular resistance of the lung, (6) reduced one or more inflammatory signaling pathways (e.g., an IL-8, Endothelin-1, IL-6, STAT-3, IL-1, mTOR, eNOS, TNFR2, TNFR1, and/or NF-KB signaling pathway). The prior art is also silent as to an ex vivo lung exposed to weeks or months of either cold ischemia or ex vivo perfusion being administered isolated mitochondria, instead restraining both to less than 48 hours.
These aspects of using 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 or unreasonable burden being on such artisan.
The prior art teaches arctic ground squirrels can have a body temperature below freezing (Williams et al., Physiol Biochem Zool 85(4):397-404 (2012) at Fig. 3), which raise the question of what conditions represent “cold” ischemia to such a squirrel’s lung. As the instant application provides no evidence of achieving the recited effects after exposing such a lung to any type of cold ischemia, this extreme situation is not enabled.
The amount of direction and guidance as well as any working examples provided:
The instant specification provides a single working example that produces the results (1)-(4) recited in claim 69 wherein only mammalian mitochondria and mammalian lungs of the same biological species (porcine) were used and wherein the perfusion step comprises ventilation, restoring physiological temperature (rewarming), and a deoxygenated and buffered perfusate wherein the mitochondria are administered by perfusion and the total perfusion duration is at least for 5 hours (Example 11, FIG. 40-43). The same is the only working example provided for the additional/narrower results recited in claims 544, 547-548, 550-551 and 569-573. Moreover, Applicant’s own arguments in the record stress this: there is a lack of guidance in the prior art of ex vivo lung perfusion methods for small and fragile lungs, such as, e.g., lungs of mice or amphibians (see end of pg. 12 of response filed 1/5/26).
Nowhere does the instant specification show or even provide guidance as to how to apply the claimed method to a non-mammalian lung (e.g., invertebrate lungs) or using nonmammalian mitochondria (e.g., fungal or plant), or wherein the perfusion step lacks physiological conditions, ventilation, and an oxygenated perfusate over a several hours. Thus, there is no evidence in the instant application or the prior art that the scope of the claimed method is realistic ensured to produce all, or even any, of the effects recited in claim 69, especially for a lung exposed ex vivo to at least 12 hours of cold ischemia.
Undue experimentation would be required to fill these gaps and unpredictability. Undue experimentation is required to determine the entire scope of methods to achieve after 12 hours of cold ischemia: (1) reduces expression of a reactive oxygen species (ROS)-induced DNA activation maker, (2) increases expression of one or more gap junction markers, (3) reduces one or more inflammatory signaling pathways and (4) reduces production of one or more inflammatory cytokines in the ex vivo lung; and may never actually be achievable across the full scope of any lung, any mitochondria, any perfusion conditions, and/or any mitochondria delivering option.
In summary, the claims are rejected under 35 U.S.C. 112(a) because the specification does not reasonably provide enablement to a person skilled in the art to perform claim 69 having method steps of high generality to predictably produce any one of: (1) reduces expression of a reactive oxygen species (ROS)-induced DNA activation maker, (2) increases expression of one or more gap junction markers, (3) reduces one or more inflammatory signaling pathways or (4) reduces production of one or more inflammatory cytokines in the ex vivo lung across the full scope of the claims. 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, undue and/or unreasonable experimentation would have been required.
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.
Claim 574 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant) regards as the invention.
Claim 69 recites the relative term “cold” in the phrase “cold ischemia.” The term “cold” is indefinite for being relative and not anchored to any baseline or reference temperate because neither the claim nor the specification provides a standard or means for determining a boundary for a “cold” temperature to inform the skilled artisan of the metes and bounds of this limitation. For example, the temperature representing “cold” to a cold-blooded animal’s lung might require an operational definition. Claims 543-544, 546-551, 556-559, and 568-575 are included in this rejection for depending on indefinite claim 1.
Claim 574 recites the trademark/trade name “Steen.” Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name STEEN® is used to describe the structural characteristics of a solution, the description is indefinite.
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 543-544, 547-548, 550-551, and 569-573 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.
Claims 543, 546, 549, and 568 each attempts to narrow the scope of claim 69 to wherein said delivering produces an alternatively recited effect of claim 69; however each of these effects either inherently occurs by performing the method of claim 69 or each of claims 543, 546, 549, and 568 lacks sufficient written description of the claimed method (see 112(a) section above).
Claims 544, 547-548, 550-551, and 569-573 each attempts to narrow the scope of claim 69 to wherein said delivering produces a specifically recited result; however each of these results either inherently occurs or each of claims 544, 547-548, 550-551, and 569-573 lacks sufficient written description of the claimed method (see 112(a) section above).
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 69, 543-544, 546-551, 556-559, and 568-575 are rejected under 35 U.S.C. 103 as being unpatentable over McCully (WO2017124037A1) in view of Becker (Becker et al., Transpl Int 29: 88-97 (2016)) and Yivgi-Ohana (US 20140193511 A1).
Regarding claim 69, McCully teaches that organ damage from cold (~4 °C) ischemia is an important issue during organ transplantation procedures because organs, including lungs, subjected to lengthy periods of cold ischemic storage followed by reperfusion often sustain mitochondrial damage, which has a negative impact on oxygen consumption and energy synthesis negatively affecting tissue survival and lung function (pg. 37, lines 1-14; pg. 29, lines 31-33; pg. 2, lines 10-14). McCully expressly teaches exposing ex vivo organs (e.g., of pigs) to isolated mitochondria after the organ is retrieved form a donor but before the organ is transplanted into a recipient (pg. 38, lines 5-7; pg. 35, lines 21-30; pg. 9, lines 25-31), such as to minimize ischemia/reperfusion damage (pg. 5, line 27, to pg. 6, line 1; pg. 21, lines 4-8; pg. 37, lines 1-14 and 19-21) by administration the mitochondria via perfusion (pg. 5, line 27, to pg. 6, line 1; claim 52) or any method known in the art (pg. 35, lines 30-31; pg. 39, lines 8-9), including perfusing the organ ex vivo with a solution comprising the mitochondria (pg. 36, lines 4-21; pg. 37, lines 14-17; pg. 30, lines 4-5). McCully expressly teaches delivering the isolated mitochondria during ex vivo organ perfusion prior to transplantation to enhance survival of the organ and/or to improve functional performance of an organ, e.g., by specifically increasing oxygen delivery capacity (pg. 35, lines 21-30; pg. 37, line 29, to pg. 38, line 2; pg. 30, lines 15-16). McCully teaches administering the mitochondria periodically, such as every two or 12 hours (pg. 40, lines 29-32; pg. 27, lines 27-30; Examples 7 and 12). In particular, McCully teaches delivering isolated mitochondria to an ex vivo lung (pg. 6, lines 28-32) to treat cold ischemia injuries (pg. 29, line 31, to pg. 30, line 2-3; pg. 37, lines 1-14; pg. 69, lines 16-18), such as injuries occurring during a lung transplant procedure in order to enhance survival and/or improve function of the transplanted lung (pg. 5, lines 26-30; pg. 20, lines 29-31; pg. 37, lines 14-21). McCully presents data supporting these methods can benefit lungs by empirically showing delivering isolated mitochondria to lungs before or after ischemia / reperfusion damage resulted in benefits regarding lung ischemia reperfusion injuries, e.g., better lung structure and function in a mouse model (Example 13; FIG. 31A-B).
Regarding claim 69, McCully does not teach (1) wherein the lung has been exposed ex vivo to specifically at least 12 hours of cold ischemia, (2) wherein the isolated mitochondria are stored prior to the delivering at a temperature from about -70°C to about -100°C for at least 24 hours, or (3) wherein the delivering produces at least one of the following effects ex vivo in the lung: reduces expression of a reactive oxygen species (ROS)-induced DNA activation maker, increases expression of one or more gap junction markers, reduces one or more inflammatory signaling pathways, reduces production of one or more inflammatory cytokines, and reduces pulmonary vascular resistance (PVR).
However Becker teaches exposing an ex vivo lung to cold ischemia for 24 hours followed by EVLP (ex vivo lung perfusion) successfully preserved lung anatomy physiological function (Abstract, pg. 89, right col., para. 2, to pg. 91, left col., Fig. 1-7). Further, Becker teaches desires to expand the number of lungs available for clinical use by better preserving marginal lungs and undertake experimental techniques to alleviate the scarcity of lungs, such as by improving transplantation rates and expanding the donor pool to encompass more “marginal” donor conditions (pg. 88, right col., to pg. 89, left col., 1st para.).
Yivgi-Ohana teaches storing isolated mitochondria at a temperature from about -70°C to -80°C for 24 hours to a month ([0026]-[0027], [0078], [0182]-[0183]; [0190]) and that subjecting purified mitochondria to a freezing and thawing process improves oxygen consumption by the mitochondria ([0027]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to modify a method of delivering isolated mammalian mitochondria to a porcine lung ex vivo as taught by McCully after exposure to cold ischemia for as much as 24 hours (e.g., 12-24 hours) as taught by Becker to also include freezing the isolated mitochondria from about -70°C to -80°C for 24 hours to a month and then thawing the isolated mitochondria prior to the delivering as taught by Yivgi-Ohana. One of ordinary skill in the art would be motivated to do so with a reasonable expectation of success because Becker teaches applying EVLP after 24 hours cold ischemia preserves lungs, Yivgi-Ohana teaches freezing/thawing isolated mitochondria increasing oxygen consumption and McCully teaches treating lungs with isolated mitochondria to mitigate damage caused by cold ischemia and/or perfusion, such as by increasing oxygen usage via delivering additional mitochondria to the lung (pg. 37, lines 1-21). As to the method of delivery, McCully teaches various types of administrating isolated mitochondria, including during reperfusion (pg. 38, lines 8-11; pg. 36, lines 4-21; Example 13). One of ordinary skill in the art would be motivated by Becker to improve lung preservation methods by using EVLP after as much as 24 hours of cold ischemia and by McCully to minimize cold ischemia damage by administering isolated mitochondria, which conveniently maybe performed together (i.e., adding the mitochondria to the perfusate) or alternatively by injecting the mitochondria into the lung or liquid in which the lung is submerged during reperfusion (pg. 30, lines 4-5). Note, an overlapping range between the prior art and a claim provides a prima facie case of obviousness (see MPEP 2144.05), and as remarked above, 12-24 hours overlaps at least 12 hours, about -70 to -80°C overlaps about -70 to -100 °C, and 24 hours to a month overlaps at least 24 hours. Thus, the method as positively recited in claim 69 is obvious in view of McCully, Becker, and Yivgi-Ohana.
Regarding claim 69, the combination of McCully, Becker, and Yivgi-Ohana does not expressly teach wherein the delivering produces at least one of the following effects in the ex vivo lung: reduces expression of a reactive oxygen species (ROS)-induced DNA activation maker, increases expression of one or more gap junction markers, reduces one or more inflammatory signaling pathways, reduces production of one or more inflammatory cytokines, and reduces pulmonary vascular resistance. However the combination of McCully, Becker, and Yivgi-Ohana teaches a process having the same positively recited method steps, thus, the claimed effects are considered based on the logic of the claim as drafted and in the absence of factual evidence to the contrary to be inherent outcomes of performing the process as positively recited by the natural laws of biology. To the extent any of these effects are argued to be absent from the method taught by the prior art laid out above, note the 112(a) rejection above.
Regarding claims 543-544, 546-551, and 568-573, the combination of McCully, Becker, and Yivgi-Ohana does not expressly teach the delivering step produces the effects recited in the claims, including reducing an expression of a ROS-induced DNA activation marker in the lung (e.g., 8-hydroxy-2'-deoxyguanosine), increasing expression of one or more gap junction markers (e.g., JAM1 and CD31), reducing an apoptosis signaling pathway in the lung, reducing production of one or more cytokines in the lung (e.g., IL-6 and/or IL-8), reducing a pulmonary vascular resistance, reducing one or more inflammatory signaling pathways (e.g., an IL-8, Endothelin-1, IL-6, STAT-3, IL-1, mTOR, eNOS, TNFR2, TNFR1, and/or NF-KB signaling pathway). However the combination of McCully, Becker, and Yivgi-Ohana teaches the same method steps and, thus, all the recited effects are expected to necessarily and naturally flow from performing the method as taught by McCully and Yivgi-Ohana. To the extent any of these effects are argued to be absent from the method taught by the prior art, then the active steps as recited the claims lack sufficient written description 112(a) to ensure the recited effects would predictably occur.
Regarding claims 556-558, McCully teaches administering isolated mitochondria periodically, e.g., every 2 hours or every 12-24 hours (pg. 40, lines 29-32; pg. 27, lines 27-30; Examples 7 and 12). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to apply a method of delivering isolated mitochondria to a lung ex vivo after exposure to at least 8 hours of cold ischemia as taught by McCully, Becker, and Yivgi-Ohana to include administering the mitochondria at hour 2, 4, 6, 8, 12, 16, 18, 20, 22, and/or 24 after the cold ischemia, such as administering periodically from hour 2 to hour 24 at intervals of 2 hours or merely every 24 hours starting with the EVLP solution that ends the cold ischemia. One of ordinary skill in the art would be motivated to do so because McCully teaches it takes at least 4-5 hours for exogenous mitochondria to integrate with the endogenous mitochondria, whereas shorter times showed only the beginnings of endocytosis of the exogenous mitochondria (pg. 60, lines 23-24; FIG. 6), and teaches for treating damage to administer the mitochondria continuously and indefinitely until no longer necessary (pg. 26, lines 24-26). Note, an overlapping range between the prior art (e.g., every 2 hours from 2-24 hours) and a claim provides a prima facie case of obviousness (see MPEP 2144.05).
Regarding claim 559, McCully teaches administering isolated mitochondria periodically, e.g., every 12-24 hours (pg. 27, lines 27-30). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to apply a method of delivering isolated mitochondria to a lung ex vivo after exposure to at least 8 hours of cold ischemia as taught by McCully, Becker, and Yivgi-Ohana to include administering the mitochondria at over 3 hours after commencement of EVLP (e.g., at hour 4, 6, 8, 12, 16, 18, 20, 22, and/or 24 after the cold ischemia is ended by the EVLP), such as wherein the mitochondria are administered at both an hour 0 and hour 24 as defied by initiation of EVLP, e.g., at hour 0 in a wash solution (pg. 36, lines 8-13; pg. 21, lines 4-5; pg. 38, lines 8-11; pg. 21, lines 4-8) or perfusate solution and at hour 24 in perfusate solution (pg. 36, lines 4-21) and optionally in-between at intervals (e.g., every 2 or 12 hours). One of ordinary skill in the art would be motivated to optimize ex vivo lung preservation/health, such as for use in transplantation, and McCully methods are taught to enhance lung survival, improve lung function, and reduce mitochondrial oxidative damage (pg. 5, lines 26-30; pg. 20, lines 29-31; pg. 37, lines 14-21) and to treat/reduce cold ischemia injuries or mitochondria damage caused by ischemia/reperfusion (pg. 29, line 31, to pg. 30, line 3; pg. 37, lines 1-14; pg. 69, lines 16-18). Furthermore, McCully teaches delivering isolated mitochondria after ischemia and/or reperfusion to minimize damage as well as administering the mitochondria indefinitely to treat damage until no longer necessary (pg. 26, lines 24-26), which includes administering the mitochondria for 3 or more hours after ending the cold ischemia (e.g., up to 12-24 hours or more as need to reduce lung damage).
Regarding claim 574, McCully does not teach wherein the ex vivo lung perfusion comprises perfusing with a Steen solution.
However Beckers teaches the EVLP process commonly comprises perfusion with STEEN Solution™, and tested their method using a Steen solution after 24 hours of cold ischemia, either with or without erythrocytes (pg. 88, right col.; pg. 89, left col., 2nd para.; pg. 89, right col., 4th para.). Thus it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to perform the method taught by the combination of McCully, Beckers, and Yivgi-Ohana to use an EVLP perfusate specifically comprising a Steen solution. One of ordinary skill in the art would be motivated to do so because Beckers teaches using Steen solutions as perfusates during EVLP to successfully preserve ex vivo lungs after cold ischemia for 24 hours (Abstract, pg. 89, right col., para. 2, to pg. 91, left col., Fig. 1-7).
Regarding claim 575, as set forth above for claim 69, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to modify a method of delivering isolated mitochondria to a lung during EVLP as taught by McCully after exposure to cold ischemia for at least 15 hours (e.g., 15-24 hours) as taught by Becker to also include freezing the isolated mitochondria from about -70°C to -80°C for 24 hours to a month and then thawing the isolated mitochondria prior to the delivering as taught by Yivgi-Ohana. One of ordinary skill in the art would be motivated to do so with a reasonable expectation of success because Becker teaches applying EVLP after 24 hours of cold ischemia preserves lungs, Yivgi-Ohana teaches freezing/thawing isolated mitochondria increasing oxygen consumption and McCully teaches treating lungs with isolated mitochondria to mitigate damage caused by cold ischemia and/or perfusion, such as by increasing oxygen usage via delivering additional mitochondria to the lung (pg. 37, lines 1-21).
Thus, the claimed invention as a whole is prima facie obvious prior to the earliest effective filing date in the absence of evidence to the contrary.
Response to Arguments
Applicant's claim amendment regarding “at least 12 hours of cold ischemia” and supporting argument in the response filed 1/5/26 (pg. 15, 2nd para.) has been found persuasive regarding Medeiros, but new grounds of obviousness are presented in this Office action. Applicant's other arguments in the response filed 1/5/26 have not been found persuasive.
Applicant traverses the obviousness rejection of the claims by arguing at pg. 7-12 that nowhere does the prior art teach the “special/unexpected” effects recited in claim 69 occurring in an ex vivo lung as well as a lack of a reasonable expectation of success of producing said effects due to the added step of exposing the lung to over 8 hours of cold ischemia prior to exposing the lung to ex vivo perfusion.
Despite arguments presented in the response at pg. 8-10, the relied upon prior art does not need to expressly teach any of the specific effects recited in claim 69 because as noted in the rejection above, the effects are considered to be inherent outcomes of performing the method steps as positively recited in claim 69. The obviousness rationale used is teaching, suggestion, or motivation (see MPEP 2143 I(G) and MPEP 2143.01) to arrive at the positively recited active method steps recited in the claims from teachings in the prior art. This is regardless of any express expectation of producing, or even reasonably implied expectation, that at least one of the effects recited in claim 69 occur in the ex vivo lung, namely: wherein delivering reduces expression of a reactive oxygen species (ROS)-induced DNA activation maker, increases expression of one or more gap junction markers, reduces an apoptosis signaling pathway, reduces one or more inflammatory signaling pathways, reduces production of one or more inflammatory cytokines, or reduces pulmonary vascular resistance (PVR).
Instead, the reasonable expectation of success established under the above obviousness rationale is to produce different effects, namely reducing damage to an ex vivo lung subjected to cold ischemia for hours, because the combination of McCully, Becker and Yivgi-Ohana reasonably predicts delivering the mitochondria will benefit an ex vivo lung already subjected to cold ischemia, such as via the expected results of increasing oxygen by increasing mitochondria function (Yivgi-Ohana at [0027]; McCully pg. 37, line 29, to pg. 38, line 2; pg. 30, lines 15-16), enhancing survival, improving lung function (pg. 5, lines 26-30; pg. 20, lines 29-31; pg. 37, lines 14-21), and reducing reperfusion damage (pg. 5, line 27, to pg. 6, line 1; pg. 21, lines 4-8), such as determined merely by visual inspection as in McCully. These beneficial effects and motivations to expand the marginal lung donor pool and preserve lung anatomy/physiology are taught in the prior art even if the effects recited in the claims are not appreciated by the prior art nor predicted to occur. Thus, prior art known method steps used to achieve prior art known result. The method rendered obvious by the prior art are the precise active steps recited independently of any intention of achieving the same specific purpose of the claims.
It is agreed that McCully does not teach any of the specific effects recited in claim 69 for ex vivo lungs and that one of ordinary skill in the art still would not have expected any of those specific effects recited in claim 69 to occur based on McCully. As noted in MPEP 2112(II), it is not required that the inherent feature or property be recognized by the prior art, and thus the conclusion that the recited effects on the lung are inherent outcomes is not based on possibilities and probabilities simply because it is relied on in an obviousness rejection using references that are completely silent as to the effects. The effects on the lungs of the method steps are considered inherent because they are considered to necessarily flow from the method steps as positively recited and taught by the prior art and based on the logic of the claims as drafted, such as wherein the dose is at least 1 x1014 mitochondria as taught by McCully (pg. 27, lines 7-30).
The teachings of Necki, Yu, Wang and Brathwaite are not persuasive in view of other prior art teachings of ex vivo lung preservations methods comprising cold ischemia (e.g., 10-24 hours) followed by ex vivo perfusion as noted above (Erasmus, ME., Pulmonary surfactant and lung transplantation (1997); Cypel et al. (2009); Pego-Fernandes et al. (2010); Becker et al. (2016) at Fig. 4, Hsin et al. (2016); Medeiros et al. (2012) at Abstract, Fig. 4, pg. 308, right col., 2nd para., to pg. 309, left col., 2nd para.). Thus, one of ordinary skill in the art would be aware of lung cold ischemia times of as long as 24 hours for mammalian lungs combined with EVLP to protect/recondition the lungs. None of Necki, Yu, Wang and Brathwaite teaches away from longer cold ischemia times to extend the donor pool of marginal lungs beyond the generally known proposition that minimizing times helps minimize damage, especially for human lung transplantation.
Applicant further submits that one of ordinary skill in the art would not be able to perform an ex vivo lung perfusion based upon McCully's only lung working embodiment using mice lungs (Example 13). However for McCully to teach various methods applied to lung, there is no need for McCully to provide any working example to be considered an enabled and operable teaching as applied to a lung ex vivo. See MPEP 2121. A reference is prior art for all that it teaches. The specification of McCully need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970). Thus, Example 13 of McCully is not limiting as to what McCully may teach about administering isolated mitochondria to a lung ex vivo and does not discourage or teach away from the method of instant claim 69 as applied to porcine lungs. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. See MPEP 2123. "The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed." Id.; see also MPEP 2141.01(VI).
Regarding the meaning of the term “ex vivo lung perfusion” as used in the claims, this is neither defined in the claims nor the instant specification. Thus, continual ventilation and normothermic temperature ranges are irrelevant to the current analysis, but applicant’s remarks here (pg. 12) are noted above regarding the current 112(a) rejections.
Applicant traverses a prima facie case obviousness rejection of the claims by arguing at pg. 13-14 evidence of surprising and unexpected results; however this is not found persuasive. No evidence of unexpected results has been provided in Example 11 and FIG. 40-43 as these data have yet to be established as unexpected/surprising. Evidence of unexpected results would take the form of comparing such results shown in Example 11 and FIG. 40-43 or similar data to the results of performing methods taught in the prior art, such as methods taught by McCully, where isolated mitochondria are not stored at low-temperature (from about -70C to about -100 C for at least 24 hours) prior to delivering to a lung in order to establish what is expected from what is unexpected. Instead, all the purported unexpected evidence presented is compared to a buffer-only negative control, which is not expected to provide any improvement. Furthermore, any such result as noted above, whether expect or unexpected, is considered to necessarily flow from performing the method steps as positively recited and taught by the prior art absence evidence to the contrary.
Furthermore, applicant has not yet established the criticality of exposing the ex vivo lung to a specific number of hours of cold ischemia (e.g., > 8, 11, 14 hours) or to any specific mitochondria delivering time window (e.g., 8-24 hours after exposing) to generating any of the purported “special” or “unexpected” effects recited in the claims.
Conclusion
No claim is allowed.
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/ERIC J ROGERS/
Examiner, Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
Prosecution Insights