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 .
DETAILED ACTION
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on October 31, 2025. Claim 4 has been canceled. Claims 38-42 have been newly added. Claims 1, 11, and 12 have been amended.
Therefore, claims 1-3, 5-14, and 34-42 are currently under examination.
Priority
The present application filed on April 06, 2022 is claiming the benefit under 35 U.S.C. 119(e) of prior-filed provisional application 63/171,858, filed on April 07, 2021.
Thus, the earliest possible priority for the instant application is April 07, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/31/2025 is acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Withdrawn Claim Rejections - 35 USC § 112(a)
Upon further consideration, and in light of applicant’s clarification the rejections 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or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement have been withdrawn.
Withdrawn- Claim Rejections - 35 USC § 103
In view of Applicants amendment to the instant claims, amending preservations times, the rejection under 35 U.S.C. 103 to claims 1-14 and 34-37 as being unpatentable over Hsin et al. (J Heart Lung Transplant. 2016 Jan;35(1):130-136.Epub 2015 Jun 1; of record IDS filed on 12/15/2023, cite no.14, hereinafter "Hsin"), in view of Wang et al. (J Thorac Cardiovasc Surg. 1989 Sep;98(3):333-42., see IDS), Date et al. (J Thorac Cardiovasc Surg. 1992 Apr;103(4):773-80., hereinafter “Date 1”), Date et al. (J Thorac Cardiovasc Surg. 1993 Mar;105(3):480-91., hereinafter “Date 2”), Kayano et al. (Circulation. 1999 Nov 9;100(19 Suppl): II257-61.), Gil et al. (US 2019/0098892 A1, hereinafter "Gil"), and Cypel et al. (J Heart Lung Transplant. 2008 Dec;27(12):1319-25; of record IDS filed on 12/15/2023, cite no.6, hereinafter "Keshavjee"). Further evidenced by Ali et al (NEJM Evid. 2023 Jun;2(6):EVIDoa2300008. Epub 2023 Apr 20.) has been withdrawn. Applicants’ arguments are moot in view of the withdrawn rejection. A response to Applicant’s arguments pertinent to a new or remaining rejection can be found below.
New Claim Rejections - 35 USC § 103
Claims 1-3, 5-14 and 34-42 are newly rejected under 35 U.S.C.103 as being unpatentable over Hsin et al. (J Heart Lung Transplant. 2016 Jan;35(1):130-136.Epub 2015 Jun 1; of record IDS filed on 12/15/2023, cite no.14, hereinafter "Hsin"), in view of Cypel et al. (US 2012/0330438 A1, hereinafter “Cypel”), Wang et al. (J Thorac Cardiovasc Surg. 1989 Sep;98(3):333-42., see IDS), Date et al. (J Thorac Cardiovasc Surg. 1992 Apr;103(4):773-80., hereinafter “Date 1”), Date et al. (J Thorac Cardiovasc Surg. 1993 Mar;105(3):480-91., hereinafter “Date 2”), Kayano et al. (Circulation. 1999 Nov 9;100(19 Suppl): II257-61.), Gil et al. (US 2019/0098892 A1, hereinafter "Gil"), Cypel et al. (J Heart Lung Transplant. 2008 Dec;27(12):1319-25; of record IDS filed on 12/15/2023, cite no.6, hereinafter "Keshavjee"), and further in view of. Further evidenced by Ali et al (NEJM Evid. 2023 Jun;2(6):EVIDoa2300008. Epub 2023 Apr 20.).
Regarding claim 1-3, and 38-42, Hsin teaches a method where donor lungs are retrieved from a donor and perfused with cold Perfadex via the pulmonary artery. After explanation, the organ is further perfused with Perfadex via a retrograde flush. The lungs are then refrigerated by placement in cold static preservation (CSP) by being stored inflated in cold Perfadex for a CIT-1 of 10 hours (refrigeration step 1). At the end of CIT-1, all study lungs undergo normothermic, 37°C, acellular ex vivo lung perfusion (EVLP or EVOP) for 6 hours (perfusion step 1). After EVLP, the lungs are placed in CSP a second time (CIT-2) by cooling them down while in the circuit to 10°C and then placed in cold Perfadex at 4°C. (page 131; col. 1, last two paragraphs) (perfusion step 2). Moreover, Hsin teaches multiple steps of EVLP at different temperatures and periods of time reported during the process, depending on experimental group conditions, falling within the scope of "a preserved, twice perfused donor organ" of claim 2 and "refrigerating the twice-perfused donor organ to form a third-refrigerated donor organ" of claim 3 (Abstract and page 131, methods section: Donor lung and EVLP procedures).
Regarding the methodological selection of alternatively claimed preservation times, such as 26 hours, refrigeration times or rounds of 12 hours increments, or a total method of preserving for at least 72 hours, these transplant temporal optimizations are routine and deemed merely a matter of judicious selection and routine optimization that is well within the purview of skilled artisan, in view of Cypel. Cypel explicitly teaches this methodological application, stating
“Organs subjected to EVOP can be preserved and maintained for 12, 24, 72 hours, or longer.” ([0028])
Hence, Cypel expressly teaches that organs subjected to ex vivo organ perfusion systems can be preserved for extended periods of time, including 12, 24, 72 hours or longer. The ordinary artisan would have been further motivated by such teaching in the prior art and had a reasonable expectation for extending the preservation protocol, such as that taught by Hsin, to clinically useful extended durations, such as 48 or 72 hours.
Concerning the limitation of “refrigerating a donor organ at 8-12 °C prior to any perfusion of the donor organ to form a once-refrigerated donor organ”, Hsin expressly teaches at the end of EVLP, the lungs were placed in cold static preservation a second time by cooling them down while in the circuit to 10°C (pg. 131, column 1, last para.).
Hsin does not expressly teach that during the first CIT-1, cold ischemic time (refrigeration period), the temperature was between 8-l2°C. Instead, the teachings of Hsin are primary addressed to investigating the impact of CIT-2, concluding that,
"In this pre-clinical porcine model of lung transplantation after EVLP, we have demonstrated that the performance of donor lungs that underwent a long CIT-2 was as good as the performance of lungs that underwent a short CIT-2. Additionally, lungs that underwent a long CIT-2 showed comparable acute lung injury scores, inflammatory cytokine levels, and caspase-3 activation compared with the short CIT-2 group. Both EVLP groups had better lung function and decreased cell death markers compared with prolonged CIT alone, which suggests that the intervention of EVLP itself at some point during the preservation process leads to improved graft function after transplantation, regardless of CIT."
However, the ordinary artisan would have recognized 10℃ as an optimal temperature for static lung preservation and the impact on reactions of the mitochondria, further in view of Wang, Date 1, Date 2, Kayano and Gil.
Wang teaches “(1) The degree of impaired lung function produced by ischemia is reflected by a decrease in oxygen uptake and in oxygen tension of the effluent pulmonary venous blood and an increase in pulmonary artery perfusion pressure; (2) hypothermia improves ischemic tolerance; (3) preservation of lung at 10° C is superior to preservation at 15° C and 4° C (Abstract).
Date 1 also clearly teaches “(1) Optimal temperature for lung preservation is in the vicinity of 10° C, and (2) lung dysfunction caused by excessive hypothermia is not due to a failure to maintain adenosine triphosphate levels.
Date 2 similarly teaches “lung preservation at 10° C with low-potassium dextran solution with 1 % glucose solution is associated with continuation of normal glucose metabolism via the glycolytic pathway and aerobic metabolism through the citric acid cycle” (Abstract).
Kayano similarly taught optimal conditions for lung graft storage, identifying storge at 10℃ (Abstract).
Gil expressly teaches an organ perfusion device for pumping perfusate through an organ (claim 1 and [0076]), and "when organ is a lung or pair of lungs, it is desirable to maintain the preservation fluid at a temperature of about ten degrees Celsius ([0076])."
Hence, before the effective filing date, the ordinary artisan would have been motivated to apply the known technique of storing or refrigerating a donor organ at 10℃, which is between 8-12°C, as taught by Cypel, Wang, Date 1, Date 2, Gil and Kayno, to the perfusion methodology, as taught by Hsin, ready for improvement to yield predictable results. The motivations for such a modification stem from the recognition that studies performed over 30 years ago identified 10℃ to be an optimal temperature for static lung preservation. The following reference is cited as evidence without relying on the rejection. Ali et al. explicitly states:
“Previous studies performed over 30 years ago identified 10℃ to be an optimal temperature for static lung preservation. Recently, this concept has been revisited, with preclinical data showing that static lung storage at 10℃ leads to excellent graft function after a prolonged storage period in excess of 24 hours. Moreover, lung preservation at 10℃ was associated with an improved inflammatory profile, improved mitochondrial health, and maintenance of cellular membrane function in comparison with the conventional ice cooler approach. A pilot study including five patients at a single center was performed to evaluate the feasibility of 10℃ static lung preservation to intentionally prolong preservation times in order to allow for the avoidance of overnight transplantation.”
Furthermore, it is no more than routine experimentation for one of ordinary skill in the art to discover an optimum value for a result effective variable (MPEP 2144.05). That is to say that the particular parameter was taught and known to affect the result. Generally, differences in temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955). In the instant case, it is clear that temperature was an established result effective variable for optimal donor lung preservation for transplantation.
Regarding claims 5-7, the combined teachings of Hsin, Cypel, Wang, Date 1, Date 2, and Gil render claim 1 obvious. Hsin teaches that during EVLP, ex vivo lung function is assessed by oxygenation, airway pressure, lung compliance, and pulmonary artery pressure (page 131, column 1, para. 3-4). Hsin also teaches normothermic ex vivo lung perfusion for 6 hours, which the practitioner in the art would readily understand refers to normal physiological temperature or 37°C "At the end of CIT- 1, all study lungs underwent normothermic acellular EVLP, as previously described,' for 6 hours." (Page 131, col. 1, para. 3). Additionally, Gil teaches ventilation of the organ ([0062- 0065] and claim 20), and the use of the module at the normothermic temperature of 37°C (instant claims 6 and 12, in part) ([0035]). Concerning claim 7, Hsin teaches lungs were then transplanted and reperfused for 4 hours and assessed for function (Abstract and page 131, methods section: Donor lung and EVLP procedures).
Regarding claims 8-10 and 14, the combined teachings of Hsin, Cypel, Wang, Date 1, Date 2, and Gil render claim 1 obvious. Hsin’s steps also teach the perfusion step simultaneously serves as a refrigeration step, when conducted at appropriately cool temperatures. Hsin simultaneously teaches the organ is placed in cold Perfadex at 4°C (refrigeration step 3). Hsin discloses CIT-2 to be conducted for two different durations, in two different groups, a short CIT-2 (2 hrs.) and a long CIT-2 (10 hrs.) (pg. 131, column 1 last para. and Fig. 1). Additionally, Gil teaches the use of the module at the normothermic temperature of 37°C ([0035]).
Regarding claims 11 and 12, the combined teachings of Hsin, Cypel, Wang, Date 1, Date 2, and Gil render the limitations of claim 1 and 4 obvious. Of note, claims 11 and 12 present the limitations of the perfusate being 8-12°C and 34-40°C, while parent claims 1 and 4 only generally address a once-perfused donor organ. Still, these limitations are rendered obvious by the teachings of Hsin, as this reference teaches the perfusion step simultaneously serving as a refrigeration step and where the perfusate temperature is adjustable from ranges including 10°C and normothermic temperatures (37°C) (Abstract and page 131, methods section: Donor lung and EVLP procedures). The teachings of refrigeration using a perfusate of l 0°C and normothermic temperatures (3 7°C) have already been clarified.
Regarding claim 13, the combined teachings of Hsin, Cypel, Wang, Date 1, Date 2, and Gil do not expressly teach wherein the method is performed over a total time period of fer at least 48 hours. However, it would have been obvious to one of ordinary skill in the art at the time of the invention to combine the teachings of Hsin, Wang, Date 1, Date 2, and Gil to achieve extended preservation of a donor organ for a defined and clinically relevant period, such as at least 48 hours, prior to transplantation. The referenced prior art teaches method of investigating and optimizing lung preservation for longer-term preservation. The combination would have been motivated by the recognized clinical benefit of enabling greater flexibility in transplantation timing and logistics. Therefore, although the precise 48-hour duration is not taught verbatim, the concept of extended preservation with appropriate refrigeration and perfusion techniques would have been within the routine capabilities of those in the field, rendering the limitation obvious.
Regarding claims 34-37, the combined teachings of Hsin, Cypel, Wang, Date 1, Date 2, and Gil render claim 1 obvious. Additionally, Hsin expressly teaches the methodology investigated and taught may have important implications for clinical implementation of EVLP, organ allocation and transportation, and transformation of lung transplantation into a semi-elective procedure. Furthermore, Gil explicitly teaches their device is employed for evaluation, treatment and transportation of a donor organ, which in the present example is a pair of lungs (e.g. human lungs) collected from a donor and destined for implantation in a recipient patient ([0019]). Gil additionally teaches the device is also configured to permit perfusion of organ with any suitable fluid (selected at least in part based on the nature of the organ being perfused) to enable the above-mentioned evaluation and treatment of organ, as well as to lengthen the available time for transportation of organ ([0020]). Further, the device is configured to be movable, for example from a donor site to a mode of transportation (e.g. an aircraft), and in turn from the mode of transportation to a recipient site (e.g. an operating room in a hospital) ([0021]).
The prior art recognized the methodological utility of a perfusion device employed at specific refrigeration periods, e.g., 1, 2 and 3, perfusion cycles, and the range of temperatures over specific time intervals of operation. The versatility of these methodological steps, including transportation were well know, further in view of the teachings of Keshavjee.
Before the effective filling date of the claimed invention, Keshavjee teaches the method of extended (12-hour) ex vivo lung perfusion (EVLP) at normothermic conditions, reperfusion for 4 hours after EVLP, and cooling steps (Abstract Background and Methods). Specifically, the disclosed experimental protocol teaches that "lungs were recovered after Perfadex flush and subjected to 12 hours of normothermic (37°C) EVLP. After this period, the lungs were cooled to 20°C in the circuit, stored in Perfadex at 4°C for 2 hours (pre-implantation period) (reading on instant claims 1, 2, 9, and 14, in part), and transplanted in order to test the impact of prolonged EVLP on lung function after transplantation (Table 1 and pg. 1320, section Experimental Protocol) and reperfused (reading on claims 3 and 4, in part) (page 132, section Evaluation of Lung Function After Transplantation). The EVLP strategy summarized in Table 1 teaches perfusion times from 0-60 minutes, ventilation, and perfusion temperatures from 0°C - 37°C, as the perfusate is pumped at temperatures cool enough to refrigerate, these steps simultaneously serve as perfusion step and refrigeration step (reading on claims 5, 7, 8, 9, 10, 11, 12, in part).
In view of the benefits of allowing for a variety of innovative therapies by more efficiently preserving an organ's functional metabolic processes (normothermia), before the effective filing date of the claimed application, the ordinary artisan would have been motivated to combine the devices and functions taught by Hsin and Gil with the settings or methods (temperatures and cycles) taught by Keshavjee to yield a versatile and predictable method of lung preservation for transplantation.
Response to Applicants’ arguments as they apply to the rejection of claims 1-3 and 5-14 and 34-42 under 35 USC § 103
Applicant’s arguments filed October 31, 2025, have been fully considered but they are not persuasive.
At pages 5-15 of the remarks filed on October 31, 2025, Applicants essentially argue the following:
Applicant again argues Hsin and Gil fail to disclose or suggest the initial refrigeration step of 8-12 °C.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
This argument is not persuasive because the cited prior art demonstrates that 10 ℃ had already been identified as an optimal ling preservation temperature decades earlier.
This argument has already been responded to, in the last office action.
Please see text from the last action:
Additionally, applicant has filed a declaration stating that the clinical standard prior to the applicants’ work was 4℃, and the suggestion of 10℃ previously referenced in the prior art is merely fleeting. Applicant also argues that the prevailing assumptions about mitochondrial viability, injury kinetics, and cellular repair mechanisms indicated that maximal metabolic suppression of the organ equated to maximal preservation. Additionally, applicant states,
“Thus, the prevailing understanding in organ preservation was that a storage temperature of about 4°C or less was optimal for maximal preservation. My research group surprisingly discovered that performing cold storage at a warmer temperature-8 to 12°C- can increase the duration of preservation for donor organs prior to transplant and improve physiological and metabolic functioning of donor organs compared to the clinical standard temperature of 4°C.
Applicant’s declaration stating that the standard practice in organ preservation was static cold storage at 4°C and has been for the previous 30 years has been considered.
The points raised in this declaration are not persuasive because Ali et al. (NEJM Evid. 2023 Jun;2(6):EVIDoa2300008. Epub 2023 Apr 20.) clearly evidenced that “Previous studies performed over 30 years ago identified 10℃ to be an optimal temperature for static lung preservation. Recently, this concept has been revisited...,”
Moreover, Cypel and Ali again restate this point in Campo-Cañaveral de la Cruz et al. (Arch Bronconeumol. 2023 May;59(5):282-283. Epub 2022 Nov 21). Here, the coauthors state,
“In the early years of LTx, several studies were published which evaluated the optimal storage temperature. In fact, 10℃ was found to be the ideal temperature for preservation, however, it was not implemented in clinical practice for two reasons. Firstly, because of the lack of mechanistic data explaining why a temperature of 10℃was better than storing a lung at 4℃. Secondly, it was thought that a margin of safety was needed to ensure lung tissue viability, and 10℃ stored lungs could easily warm up.”
Prior art is prior art for all that it teaches or reasonably suggests. Prior art is relevant for all that it contains, and a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, even nonpreferred embodiments. In the instant case, the prior art cited above reinforces lung preservation at an optimal temperature of 10℃ was recognized in the prior art. Furthermore, issues raised concerning the health of mitochondria are also addressed in Wang’s and Date’s teachings of the relationships between storage temperature and mitochondrial respiration and ATP synthesis, see Wang, Date 1 and Date 2.
Applicant argues the claimed extended preservation time of 48 hours is not taught or suggested.
This argument is not persuasive because the cited references collectively teach the investigation and optimization of extended lung preservation protocols using combinations of static cold storage and ex vivo prefusion. Extending preservation time to a clinically useful duration such as 48 hours would have been obvious optimization motivated by the well-recognized goal of increasing transplantation flexibility and improving logistics.
Moreover, Cypel (US 2012/0330438A1), referenced above, taches that organs preserved using ex vivo perfusion systems may be maintained 12, 24, 72 hours, or longer, demonstrating that extended preservation durations, including those exceeding 48 hours, were explicitly taught in the prior art.
Conclusion
Claims 1-3, 5-14, and 34-42 are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/J.D.L./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633