DETAILED ACTION
Applicant's amendment and response filed on 1/30/26 has been entered. Claims 79 and 97 have been canceled. Claims 78, 80, 82-83, 86-89, 91-95, and 98 are currently pending and under examination in this application based on the elected species of ACE inhibitor and temsirolimus. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
Those sections of Title 35, US code, not included in this action can be found in a previous office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 1/30/26 is in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statement has been considered by the examiner, and an initialed and signed 1449 is attached to this action.
Priority
As set forth in the previous office action, claim 92 is only entitled to the filing date of the instant 371 application which is 3/28/19. See the Non-Final Action mailed on 8/19/24 for details.
Claim Rejections - 35 USC § 112
The rejection of claims 91 and 92 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in view of applicant’s amendments to the claims.
The rejection of claim 97 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the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends, is withdrawn in view of the cancellation of this claim.
Claim Rejections - 35 USC § 103
The rejection of claims 78-80, 82-83, 86-88, and 91-97 under 35 U.S.C. 103 as being unpatentable over U.S. Patent Application 2018/0249688 (Sept. 6, 2018), hereafter referred to as Ayares et al. with an effective filing date of 9/9/15, in view of Watson et al. (2012) Brit. J. Anaesth., Vol. 108(S1), i29-i42, Sanchez-Lazaro et al. (2008) Transplant. Proc., Vol. 50, 3051-3052, Klintmalm et al. (2014) J. Transpl., Vol. 141, 1-45, Richter et al. (2000) J. Heart. Lung. Transplant., Vol. 19(11) 1047-1055, Cooper et al. ( 2014) Xenotransplant., Vol. 21, 397-419, Trotter et al. (2001) Liver Transplantation, Vol. 7(4), 343-351, Brenner et al. (2017) Transplantation, Vol. 101(5S-3), page S65, Abstract 310.5, and Hinrichs et al. (2017) Xenotransplantation 24:pages 39–40, is withdrawn in view of either the cancellation of the claims or the amendments to the claims which now recite the additional step of transplanting the heart to a recipient organism which has been cooled to 34oC which is not taught by the cited references.
The rejection of claims 89 and 98 under 35 U.S.C. 103 as being unpatentable over U.S. Patent Application 2018/0249688 (Sept. 6, 2018), hereafter referred to as Ayares et al. with an effective filing date of 9/9/15, in view of Watson et al. (2012) Brit. J. Anaesth., Vol. 108(S1), i29-i42, Sanchez-Lazaro et al. (2008) Transplant. Proc., Vol. 50, 3051-3052, Klintmalm et al. (2014) J. Transpl., Vol. 141, 1-45, Richter et al. (2000) J. Heart. Lung. Transplant., Vol. 19(11) 1047-1055, Cooper et al. ( 2014) Xenotransplant., Vol. 21, 397-419, Trotter et al. (2001) Liver Transplantation, Vol. 7(4), 343-351, Brenner et al. (2017) Transplantation, Vol. 101(5S-3), page S65, Abstract 310.5, and Hinrichs et al. (2017) Xenotransplantation 24:pages 39–40, as applied to claims 78-80, 82-83, 86-88, and 91-97 above, and further in view of Kaplan et al. (2014) Transp. Rev., Vol. 28, 126-133, is withdrawn in view of applicant’s amendments to the claims.
Applicant’s amendments to the claims have necessitated the following new grounds of rejection.
Claims 78, 80, 82-83, 86-88, and 91-95 are newly rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent Application 2018/0249688 (Sept. 6, 2018), hereafter referred to as Ayares et al. with an effective filing date of 9/9/15, in view of Watson et al. (2012) Brit. J. Anaesth., Vol. 108(S1), i29-i42, Sanchez-Lazaro et al. (2008) Transplant. Proc., Vol. 50, 3051-3052, Klintmalm et al. (2014) J. Transpl., Vol. 141, 1-45, Richter et al. (2000) J. Heart. Lung. Transplant., Vol. 19(11) 1047-1055, Cooper et al. ( 2014) Xenotransplant., Vol. 21, 397-419, Trotter et al. (2001) Liver Transplantation, Vol. 7(4), 343-351, Brenner et al. (2017) Transplantation, Vol. 101(5S-3), page S65, Abstract 310.5, Hinrichs et al. (2017) Xenotransplantation 24:pages 39–40, and Nussmeier et al. (2005) Tex. Heart Inst. J., Vol. 32, 472-476.
Ayares et al. teaches transgenic pigs whose organs can be used for xenotransplantation, including orthotopic transplantation, into primate such as a baboon or a human (Ayares et al., entire document and in particular paragraphs 475-476, 511, 514, and 524-527). Ayares et al. teaches that the pig organs for transplant include hearts (Ayares et al., paragraph 39 and 524-527). Ayares et al. teaches that the transgenic pigs have been genetically modified to reduce acute and cell mediated rejection, including knockout of alpha-galactosyltransferase (referred to as GGTA1), and insertion in the GGTA1 locus of 4-6 transgenes including thrombomodulin (referred to as TBM), and various complement inhibitory proteins such as hCD46, hCD55, and/or hCD59 (Ayares et al., paragraphs 24-28, 37, 134, 207). Ayares et al. also teaches that the transgenic pigs may have an additional knock-out of a porcine gene (Ayares et al., paragraph 35). In particular, Ayares et al. teaches insertion of a combination of TBM and CD46 genes into a GTKO (GGTA1 knockout) pig (Ayares et al., paragraphs 69, 84, and 532). Ayares et al. also teaches that the inserted transgenes can be under control of the endogenous promoter of the target locus (Ayares et al., paragraphs 273 and 532). Ayares et al. further teaches the administration of one or more immunosuppressive drugs before, during, and after transplantation including the administration of various mTOR inhibitors such as everolimus and sirolimus, and methylprednisolone, a glucocorticoid steroid with both immunosuppressive and anti-inflammatory properties (Ayares et al., paragraphs 486-487). Ayares et al. teaches the use of one or more immunosuppressive agents/drugs for induction therapy prior to transplantation, and then a combination of agents post-transplantation including sirolimus, particularly low-dose sirolimus, for maintenance therapy (Ayares et al., paragraph 487). Ayares et al. demonstrates that 6GE pig hearts transplanted heterotopically into baboons survived greater than greater than 6-10 months, and kidneys transplanted orthotopically survived for greater than 8 months (Ayares et al., paragraphs 514, and 524).
Ayares et al. differs from the instant invention in that Ayares et al. does not teach to administer an mTOR inhibitor which is temsirolimus. Ayares et al. teaches to administer sirolimus, not temsirolimus. However, at the time of filing, a number of mTOR inhibitors were known in the art that exhibit similar activities. Watson et al. teaches that various mTOR inhibitors such as sirolimus (formerly rapamycin) and everolimus, an analogue of sirolimus, have been approved for use in renal and heart transplants, where they have been shown to reduce immune-mediated vasculopathy (Watson et al., page i31). Watson et al. further teaches that temsirolimus, another analogue of sirolimus, has the added benefit of having anti-tumor properties and can be used in patients who require transplantation due to tumor, or who develop post-transplant tumors (Watson et al., page i31). As such, in view of the availability of various mTOR inhibitors with art recognized use post-transplant as immunosuppressive and anti-inflammatory agents, including temsirolimus which has added benefit as an anti-tumor agent, the rejection of record concluded that it would have been prima facie obvious to the skilled artisan at the time of filing to substitute temsirolimus for sirolimus in the methods of Ayares et al. with a reasonable expectation of success.
Ayares et al. and Watson et al. further differs from the instant invention by not teaching to administer an anti-hypertensive agent as part of a post-transplant regimen. Sanchez-Lazaro et al. supplements Ayares et al. and Watson et al. by teaching that hypertension is common post-heart transplant and presents an analysis of heart transplantation data showing that while hypertension was present in 33.3% of patients prior to transplant, hypertension increased to 71.1% after heart transplant (Sanchez-Lazaro et al., page 3051). Sanchez-Lazaro et al. further teaches the administration of anti-hypertensives in addition to immunosuppressive agents post-transplant, including the administration of an angiotensin-converting enzyme (ACE) inhibitor as the anti-hypertensive agent (Sanchez-Lazaro et al., page 3052). Klintmalm et al. teaches the combined use of an mTOR such as sirolimus or everolimus and an anti-hypertensive agent after liver transplantation (Klintmalm et al., pages 32 and 35). Richter et al. further teaches that the use of ACE inhibitors, such as Enalapril, post-transplant has the added benefit of reducing neointimal proliferation in a heart transplant model (Richter et al., page 1047). As such, in view of the prevalence of post-transplant hypertension, and the teachings and motivation to combine the use of mTOR inhibitors and anti-hypertensives, particularly ACE inhibitors, post-transplant to treat hypertension and further reduce neointimal proliferation, it would have been prima facie obvious to the skilled artisan at the time of filing modify the methods of Ayares et al. in view of Watson et al. to include the administration of an anti-hypertensive agent which is an ACE inhibitor post-transplant with a reasonable expectation of success. Furthermore, in regards to the timing of administration of the anti-hypertensive, as Sanchez-Lozaro et al. teaches that a significant proportion of patients have pre-existing hypertension and are already taking an anti-hypertensive agent prior to transplant, and that more than 70% of patients exhibit hypertension post-transplant, it would have been prima facie obvious to the skilled artisan at the time of filing to begin the re-administration of an anti-hypertensive agent such as an ACE inhibitor immediately after transplant, i.e. within 2 days as recited in claim 87, in order to both ameliorate pre-existing symptoms of hypertension in the patient and prevent the development of post-transplant hypertension in all patients with a reasonable expectation of success.
In regards to functional substitution of a heart in a recipient and particularly where the non-human living primate has an orthotopic pig heart transplant functional for more than 60 days, it is noted that Cooper et al. teaches that the orthotopic transplantation of genetically modified pig hearts (GTKO/CD55) to baboons using an immunosuppressive regimen that included the mTOR inhibitor rapamycin (sirolimus) was functional for up to 57 days (see Cooper et al., Table I, page 402- referencing a study by Byrne). Ayares et al., however, teaches that additional modification of the pig donor through insertion of additional complement regulatory and immunomodulatory genes can increase the survival of orthotopic solid organ transplants. For example, Ayares et al. teaches that while a kidney from a three-gene GTKO.CD46.TBM pig transplanted orthotopically into a baboon survived less than 3 months, the use of a donor kidney from a 6GE pig with the genotype GTKO.hCD46.hDAF.hEPCR.hCD47.hTFPF substantially increased the orthotopic survival of the organ to greater than 8 months (Ayares et al., paragraph 514). Ayares et al., as noted above also teaches that donor hearts from 6GE pigs which include the TBM gene survived more than 10 months after heterotopic transplantation. Thus, based on the demonstration from Ayares et al. that expression of increased numbers of immunomodulatory/complement modulatory proteins can increase the survival and function of organs such as pig hearts when transplanted both heterotopically and orthotopically, and the teachings of Cooper et al. that pig hearts from GTKO.CD55 pigs can survive up to 57 days, the skilled artisan at the time of filing would have had a reasonable expectation of success in functionally substituting a 6GE pig heart for a baboon heart in a baboon as taught by Ayares et al. in view of Watson, Sanchez-Lazaro, Klintmalm and Richter, where functional heart transplant survives for more than 60 days.
Trotter et al. further supplement Ayares et al., Watson et al., Sanchez-Lazaro et al., Klintmalm et al. and Richter et al. by teaching that post-transplant immunosuppressive regimens comprising the use of prednisone can have adverse side effects including hypertension, diabetes, hypercholesterolemia, and obesity, and teaches that tapering the dose of steroid can be performed without increasing rejection of the graft or patient survival (Trotter et al., page 343). In a specific protocol, Trotter teaches an immunosuppressive post-transplant regimen which includes the daily administration of sirolimus, and a 3-day tapering dosage of methylprednisolone consisting of 1g on day 1, 0.5g on days 2-3, and 0g on day 4 (Trotter et al., page 343). The 3-day taper regimen taught by Trotter et al. decreases the amount of methylprednisolone by step by a factor of more than 10 by 5 days. Trotter et al., therefore, while acknowledging the potential for adverse side-effects from prednisone teaches a specific protocol for administering this immunosuppressive post-transplant to mitigate the problems associated with high dose prednisone therapy. Therefore, based on the teachings of Ayares et al. administer an immunosuppressant such as methylprednisolone post xenotransplantation as part of the post-operative immunosuppressant protocol, and in view of the benefits of using a tapering regimen of methylprednisolone to reduce side effects as taught by Trotter, it would have been prima facie obvious to the skilled artisan at the time of filing to utilize a tapering protocol according to Trotter et al. in the methods of Ayares in view of Watson et al., Sanchez-Lazaro et al., Klintmalm et al., and Richter et al. with a reasonable expectation of success.
While several of the cited references discuss protocols for preparation of donor organs including pig organs, none of the references specifically teach to use a non-ischemic method of preserving the donor organ prior to transplantation. Brenner et al. teaches that an alternative to more widely used ischemic preservation methods for donor organs is the use of Steen’s “non-ischemic preservation technique” which uses a 8o C cold myocardial perfusion solution consists of a modified Krebs-Henseleit solution with albumin and 10% erythrocytes, hormones, and vasoactive agents, where under pressure, flow and temperature control, the heart is constantly perfused during explanation and storage time (Brenner et al., abstract). Brenner et al. teaches obtaining a heart from a genetically modified GTKO/hCD46/hTM pig and preserving it using the Steen’s technique prior to orthotopic transplantation into a baboon, where the donor heart survived up to 40 days. Steen further teaches that while perioperative cardiac xenograft dysfunction (PCXD) was an issue when using ischemic preservation techniques, PCXD was not observed using the non-ischemic preservation technique, and thus represents an important step on the way to long-term transplant survival (Brenner et al., abstract). Therefore, based on the substantial benefits to the use of non-ischemic donor organ preservation compared to traditional ischemic donor organ taught by Brenner et al., it would have been prima facie obvious to the skilled artisan at the time of filing to utilize non-ischemic donor organ preservation in the methods of orthotopic heart transplantation taught by Ayares et al. in view of Watson et al., Sanchez-Lazaro et al., Klintmalm et al., and Richter et al., with a reasonable expectation of success.
Brenner et al., in addition to teaching the benefits of using non-ischemic donor organ preservation, teaches that donor organ overgrowth of the pig heart was a problem observed after 3 weeks in the baboon (Brenner et al., abstract). Hinrichs et al also teaches that long-term survival of orthotopic cardiac xenografts in baboons is limited by continued growth of the donor organ, space restriction and associated complications, and that they inactivated the GHR gene in triple modified donor hearts to fit for a long period in a baboon’s thorax (Hinrichs et al., abstract). Hinrich et al. teaches that they used a CRISPR/Cas system to inactivate the GHR gene and that GHR knockout pigs exhibited decrease IGF1 levels and reduced body and organ growth (Hinrich et al., abstract). Hinrich et al. says that due to the reduced organ growth, organs from these pigs can be used for xenotransplantation with the expectation to grow less rapidly, and they are also inactivating the GHR gene in GTKO/hCD46/hTM pigs to produce small donor hearts for xenotransplantation into baboons (Hinrichs et al., abstract). Hinrichs et al. thus both provide substantial motivation to not only inactivate the GHR gene in pigs in order to produce smaller donor organs which would be expected to grow less rapidly in primates, but to also introduce the GHR inactivating motivation to pigs which already have additional genetic modifications such as GTKO, and hCD46 and hTM expression.
Thus, in view of the teachings of Brenner et al. and Hinrichs et al. that pig heart overgrowth is a known problem in orthotopic cardiac xenotransplantation, and the teachings of Hinrich et al. that this problem can be alleviated by knocking out the GHR gene in donor pigs, particularly genetically modified donor pigs which already have a knockout of GTKO and inserted human CD46 and TM transgenes, it would have been prima facie obvious to the skilled artisan at the time of filing to practice the methods of orthotopic cardiac xenotransplantation taught by Ayares et al. in view of Watson et al., Sanchez-Lazaro et al., Klintmalm et al., Richter et al., Cooper et al., and Trotter et al. using a genetically modified pig heart as taught by Ayares et al. which has further been modified to include a GHR knockout according to Hinrich et al. in order to reduce unwanted overgrowth of the pig heart in a recipient such as a baboon or human with a reasonable expectation of success.
Finally, in regards to the preparation of the recipient for the heart transplant, none of the cited references specifically teach to transplant the donor heart into a recipient which has been cooled to 34oC. However, at the time of filing, it was known that neurologic injury can be a devastating complication of cardiac surgery (Nussmeier). Nussmeier teaches the use of hypothermic cardiopulmonary bypass in patients undergoing heart surgeries and that cerebral cooling is an important aspect of hypothermic cardiopulmonary bypass as it is the only reliable method of neuroprotection against injuries related to cerebral ischemia (Nussmeier, page 472). Nussmeier et al. further teaches that hypothermia between 33–35 °C during cardiopulmonary bypass has well-documented neuroprotective benefits (Nussmeier, page 474). Therefore, in view of the specific benefits of inducing hypothermia to between 33–35 °C during cardiopulmonary bypass in patient undergoing heart surgery as taught by Nussmeier, it would have been prima facie obvious to the skilled artisan at the time of filing to include a step of preparing the recipient for a heart transplant where the patient is cooled to 34oC during cardiopulmonary bypass while the patient’s heart is removed and the donor heart is implanted, in the methods of in the methods of orthotopic heart transplantation taught by Ayares et al. in view of Watson et al., Sanchez-Lazaro et al., Klintmalm et al., and Richter et al., Cooper et al., Trotter et al., Hinrichs et al., and Brenner et al., with a reasonable expectation of success.
Applicant’s arguments have been considered in so far as applicant’s arguments apply to this new grounds of rejection, but have not been found persuasive. The applicant argues that independent claim 78 has been amended to recite that the recipient has been cooled to 34oC during transplantation and that the cited references do not teach this step. In response, the rejection of record cited Nussmeier et al. for providing specific motivation to cool the recipient to 34oC during transplantation by teaching that hypothermia between 33–35 °C during cardiopulmonary bypass in cardiac surgeries has well-documented neuroprotective benefits. As such, the new rejection of record provides both the teachings and motivation for including the step of cooling the patient to 34oC during heart transplantation.
The applicant further argues that the working examples demonstrate an “unexpected” increase in survival in baboons which received a pig heart which had been preserved using non-ischemic heart perfusion prior to transplant and where the baboons had been cooled to 34oC during transplantation compared to cooling to 30oC during transplantation, and which had also received the mTor inhibitor and other elements recited in claim 78. In response, the rejection of record above provides a detailed explanation of why the skilled artisan, following the specific teachings of the cited references, would have had a more than reasonable expectation of prolonged survival of a functional heart transplant using a transplantation protocol as claimed. Further, as discussed in previous office action, it is maintained that applicant’s evidence of “unexpected results” present in the specification are not in fact commensurate in scope with claimed methods. As noted in the previous office action, whether unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). In the instant case, the working example referred to by applicant involved the transplantation of a specific genetically altered pig heart, where the pig was homozygous for a GTKO knockout and transgenic for both human CD46 and human thrombomodulin, into a baboon, where the baboon was prepared using a specific pre-transplantation protocol and subsequently treated with a specific post-transplantation protocol. Table I provides the details of the complex pre and post-transplant protocols which involved the administration of numerous antibodies, inhibitors, and other compounds, and importantly were continued though the life of the transplant, including anti-CD40 ab, CD40L Fab, IL-6R ab, MMF, TNFa inhibitor, and IL-1-receptor antagonist. Further, the protocol disclosed in the working examples teaches the combined and maintained administration of temsirolimus, elanopril and metoprolol tartrate. The claims are substantially broader than the working example which provided the “unexpected” prolonged survival of the donor pig heart in the baboon. The claims are not limited to pig hearts with the genetic modifications used in the working examples, and further do not recite steps which reflect the complexity of the pre- and post- transplant protocols which involved the administration of numerous agents. The claims further are not limited to continued use of temsirolimus as the mTOR inhibitor in combination with the use of two different anti-hypertensives elanopril and metoprolol tartrate for the life of the transplanted heart. Further, as applicant’s specification categorizes the results obtained with this specific protocol as surprising, there is no evidence that such results could be obtained using other genetically modified pig hearts, or other pre and post transplantation protocols, including the use of any mTOR inhibitor and any anti-hypertensive. As such, applicant’s arguments concerning unexpected results have not been found persuasive in overcoming the rejection of record based on the breadth of claims as written and the teachings of the cited references.
Claims 89 and 98 are newly rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent Application 2018/0249688 (Sept. 6, 2018), hereafter referred to as Ayares et al. with an effective filing date of 9/9/15, in view of Watson et al. (2012) Brit. J. Anaesth., Vol. 108(S1), i29-i42, Sanchez-Lazaro et al. (2008) Transplant. Proc., Vol. 50, 3051-3052, Klintmalm et al. (2014) J. Transpl., Vol. 141, 1-45, Richter et al. (2000) J. Heart. Lung. Transplant., Vol. 19(11) 1047-1055, Cooper et al. ( 2014) Xenotransplant., Vol. 21, 397-419, Trotter et al. (2001) Liver Transplantation, Vol. 7(4), 343-351, Brenner et al. (2017) Transplantation, Vol. 101(5S-3), page S65, Abstract 310.5, Hinrichs et al. (2017) Xenotransplantation 24:pages 39–40, and Nussmeier et al. (2005) Tex. Heart Inst. J., Vol. 32, 472-476, as applied to claims 78, 80, 82-83, 86-88, and 91-95 above, and further in view of Kaplan et al. (2014) Transp. Rev., Vol. 28, 126-133
Ayares et al. in view of Watson et al., Sanchez-Lazaro et al., Klintmalm et al., Richter et al., Cooper et al., Trotter et al., Brenner et al., Hinrichs et al., and Nussmeier et al. provide the teachings and motivation for orthotopic transplantation of a genetically modified pig heart, to a baboon or human host, where the donor heart has been preserved by non-ischemic heart perfusion until transplant, where the recipient has been cooled to 34oC, where the pig heart has been genetically modified to have a knockout of GHR and where the post-transplantation treatment regimen includes both administration of an mTOR inhibitor like temsirolimus and an anti-hypertensive agent such as an ACE inhibitor, with a reasonable expectation of success in prolonged functional substitution of the heart in the host for several weeks up to several months.
While Ayares et al. and Klintmalm et al. teaches to administer an mTOR inhibitor post-transplant as maintenance therapy, they do not specify when the mTOR administration should be begin, or more specifically that it should begin within the first 4-7 days after transplant. Kaplan et al. teaches that the use of mTOR inhibitors, such as sirolimus, everolimus, and temsirolimus, as immunosuppressive agents is associated with a variety of adverse events (AE) including wound healing, hypertension, diabetes, and obesity, but that delaying the start of mTOR inhibitory therapy until 3-7 days post-transplantation and avoiding high loading doses significantly reduces the risk of impaired wound healing (Kaplan et al., page 128). Kaplan et al. further teaches to combine the delayed mTOR inhibitor regimen with anti-hypertensive therapy including administration of an ACE inhibitor (Kaplan et al., page 131).
Therefore, in view of the benefits of using a delayed mTOR administration protocol post-transplantation, the further teachings of using mTOR inhibitors as maintenance therapy , and in combination with an anti-hypertensive agent such as an ACE inhibitor, as taught by Klintmalm et al. in order to minimize adverse effects, it would have been prima facie obvious to the skilled artisan at the time of filing to start administering an mTOR inhibitor between days 4-7 post-transplantation in the methods of Ayares et al. in view of Watson et al., Sanchez-Lazaro et al., Klintmalm et al., Richter et al. ,Trotter et al., and Hinrichs et al., and to continue the use of the mTOR inhibitor as a daily maintenance therapy with a reasonable expectation of success.
In so far as applicant’s response applies to the new grounds of rejection, it is noted that applicant arguments concerning the newly added limitation regarding cooling the recipient to 34oC have been addressed in detail above, as have applicant’s arguments concerning unexpected results, and have not been found persuasive. The applicant does not separately address any specific arguments to the teachings of Kaplan et al.. As such, applicant’s arguments are not found persuasive and the rejection set forth above stands.
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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