DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1 and 25-45 are pending (claim set as filed on 09/18/2023).
Priority
This application is a 371 of PCT/EP2022/057244 filed on 03/18/2022, which has a foreign application to UK 2103890.6 filed on 03/19/2021.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 04/25/2024 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the Examiner.
Drawings
The drawings filed on 09/18/2023 have been accepted.
Abstract Objection
The abstract of the disclosure is objected to because it does not comply with the proper language and format (see MPEP 608.01(b)). Appropriate correction is required.
Applicant is reminded of the proper language and format for an abstract of the disclosure. The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words. It is important that the abstract not exceed 150 words in length since the space provided for the abstract on the computer tape used by the printer is limited. The form and legal phraseology often used in patent claims, such as “means” and “said” should be avoided. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details. The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns”, “The disclosure defined by this invention”, or “The disclosure describes”, etc.
Claim Rejections - 35 USC §112, Indefinite
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.
Claims 28 and 31-33 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 28 recites the limitation “The method of claim 1, wherein the tissue or organ-specific inflammation”. However, there is insufficient antecedent basis for this limitation in the claim because this feature was first introduced in claim 27 instead of claim 1.
Claims 31-33 recites the limitation “The method of claim 1, wherein the donor tissue or
donor organ”. However, there is insufficient antecedent basis for this limitation in the claim because this feature was first introduced in claim 29 instead of claim 1.
Claim Rejections - 35 USC §102, Anticipation
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 25-36, 38, and 40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Baulier (Amniotic Fluid-Derived Mesenchymal Stem Cells Prevent Fibrosis and Preserve Renal Function in a Preclinical Porcine Model of Kidney Transplantation, 2014 - cited by the ISA and in the IDS filed on 04/25/24).
Regarding base claims 1 and 29, Baulier teaches that “amniotic fluid-derived mesenchymal stem cells (af-MSCs), a subpopulation of multipotent cells identified in amniotic fluid, are known to secrete growth factors and anti-inflammatory cytokines. In addition, these cells are easy to collect, present higher proliferation and self-renewal rates compared with other adult stem cells (ASCs), and are suitable for banking. Consequently, af-MSCs represent a promising source of stem cells for regenerative therapies in humans. To determine the efficiency and the safety of af-MSC infusion in a preclinical porcine model of renal auto-transplantation, we injected autologous af-MSCs in the renal artery 6 days after transplantation. The af-MSC injection improved glomerular and tubular functions, leading to full renal function recovery and abrogated fibrosis development at 3 months. The strong proof of concept generated by this translational porcine model is a first step toward evaluation of af-MSC-based therapies in human kidney transplantation” (see abstract).
Regarding claims 26-28 pertaining to an organ-specific inflammation of the kidney, Baulier teaches ischemia/reperfusion occurs in acute and chronic kidney transplant where there is a decrease in oxygen supply, followed by oxidative stress injuries and inflammation after revascularization leading to transplant dysfunction (see page 809, left col.).
Regarding claim 31, Baulier teaches “in kidney transplantation, the gradually increasing gap between the number of patients awaiting a transplant and the number of donors warrants the extension of eligibility criteria to include new donors such as donors deceased after cardiac arrest” (see page 809: Introduction).
Regarding claims 25, 30, 32-36, 38, and 40, Baulier teaches “we then demonstrate ex vivo and in vivo that af-MSC injection in renal artery improves their retention in the transplanted organ and limits their dissemination. Finally, we show in vivo that af-MSC injection in the renal artery 6 days after kidney auto-transplantation strongly improves renal function recovery and prevents kidney fibrosis in a preclinical porcine model of poor graft quality, mimicking DCDs” (see page 810, left col. 2nd ¶). Baulier further teaches “a pregnant large white sow at 112 days of gestation underwent caesarean section for piglet delivery. We took 10 mL of amniotic fluid from each piglet directly across the placental tissue, and the piglets were then collected … cells were cryopreserved until injection … 1 hour of in vivo warm ischemia was induced in the left kidney by renal pedicle clamping. Next, the kidney was removed, cold flushed, and preserved at 4°C for 24 hours in UW solution. Twenty-four hours later, the left kidney was implanted into the same animal and the right kidney was removed. Six days after kidney transplantation, a saline solution (NaCl 0.9%) supplemented or not with autologous af-MSCs (1x106 cells per kilogram of body weight) was directly injected into the renal artery of the grafted kidney exposed by mid-ventral laparotomy” (see page 810: Surgical Procedure & Differentiation Studies section).
Claim Rejections - 35 USC §103, Obviousness
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 non-obviousness.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Baulier as applied to claims 1, 25-36, 38, and 40 above, and in view of Yu (WO 2013/067124 - cited by the ISA and in the IDS filed on 04/25/24).
Baulier’s teaching is discussed above as it pertains to a method of modulating an immune response comprising administering TAF MSCs.
However, Baulier does not teach: wherein the additional agent is selected from anti-inflammatory agents, immunosuppressive agents, or anti-rejection agents (claim 37).
Yu’s general disclosure relates to a method of preventing or treating rejection of a transplanted organ in an animal by administering an effective amount of mesenchymal stem cells (see abstract & see page 1).
Yu teaches “mesenchymal stern cells may be administered in combination with one or more known pharmaceutically active agents used to treat and/or prevent transplant rejection. Such agents include, but are not limited to, anti-inflammatory agents, including non-steroidal anti-inflammatory drugs (NSAIDs), steroids, immunoregulators, and immunosuppressive agents, such as, for example, cyclosporin, and anti-T-cell antibodies, and small interfering RNAs (siRNAs) that interfere with the expression of agents that exacerbate the effects of transplant rejection” (see page 9, 2nd ¶).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ or add anti-inflammatory agents, immunosuppressive agents, or anti-rejection agents such as taught by Yu in the method of Baulier. The ordinary artisan would have been motivated to do so is because Yu teaches that said agents can be used to treat and/or prevent transplant rejection. Thus, an additive effect would have been beneficial with Baulier’s af-MSCs (MPEP 2144.06(I)). The ordinary artisan would have had a reasonable expectation of success is because both of the cited references are directed to the use of mesenchymal stem cells in the treatment of rejection of organ transplantation.
Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over Baulier as applied to claims 1, 25-36, 38, and 40 above, and in view of Haas (US 2005/0042595 A1).
Baulier’s teaching is discussed above as it pertains to a method of modulating an immune response comprising administering TAF MSCs.
However, Baulier does not teach: wherein the isolated TAF MSCs are derived from an MHC/HLA-matched donor (claim 39).
Haas’ general disclosure relates to “the field of stem cell research. Specifically, the invention relates to the preservation and banking of amniotic fluid-derived cells, or multipotent amniotic fluid-derived stem cells of individuals” (see abstract & ¶ [0003]). Haas teaches mesenchymal stem cells (see ¶ [0010], [0090]). Haas teaches multi-potent amniotic fetal stem cells (MAFSC) may be harvested from amniotic fluid from pregnant females at any stage in the gestation period (see ¶ [0023]-[0027]).
Haas teaches “the amniotic fluid-derived cells can be further classified according to certain identifying features, such as by HLA typing, either before or after processing and storage. … Typing also includes any method that identifies a stem cell product in such a way that the stem cell sample may be matched to a certain individual … for sufficient matching of HLA specificities for the use by any potential recipient” (see ¶ [0040]-[0045]).
It would have been obvious to one of ordinary skill in the art to obtain or derive isolated TAF MSCs from an MHC/HLA-matched donor such as taught by Haas in the method of Baulier. The ordinary artisan would have been motivated to do so is because MHC/HLA matching of donor and recipient is routine and conventional in the art to determine the ideal donor match with compatible recipient. The ordinary artisan would have had a reasonable expectation of success is because both of the cited references are directed to the use of amniotic fluid mesenchymal stem cells.
Claims 41-45 are rejected under 35 U.S.C. 103 as being unpatentable over Baulier as applied to claims 1, 25-36, 38, and 40 above, and in view of Larsson (US 2016/0030489 A1).
Baulier’s teaching is discussed above as it pertains to a method of modulating an immune response comprising administering TAF MSCs.
However, Baulier does not teach: wherein the isolated TAF MSCs are selected to obtain TAF MSCs having the claimed characteristics as seen in claims 41-45.
Larsson’s general disclosure relates to obtaining biological material, including amniotic
fluid and cells, including at birth, and in some aspects relates to safe, high-yield collection of sterile amniotic fluid and devices and methods for the same (see abstract & ¶ [0002]-[0010]). Larsson teaches amniotic fluid was collected from a healthy pregnant woman during full term caesarean delivery where “For isolation of cells, the 400 mL amniotic fluid was filtered through a 100-micron nylon mesh to separate the vernix and larger tissue debris aggregates. The filtered material was then put onto a Ficoll 400 sucrose gradient and centrifuged at room temperature for
5 minutes at 500 g” (see ¶ [0128]-[0134]: Example 3 which is a similar process to the instant specification at Figure 1 and although Larsson is silent with regards to the claimed cell characteristics, since both use similar process to obtain the cells, this is technical reasoning to believe that Larsson’s cell population will inherently have the same characteristics as in the claims).
It would have been obvious to one of ordinary skill in the art to use the cell isolation method such as taught by Larsson in the method of Baulier. The ordinary artisan would have been motivated to do so is because Larsson teaches a safe and high-yield collection of sterile amniotic fluid cells. The ordinary artisan would have had a reasonable expectation of success is because both of the cited references are directed to amniotic fluid cells.
Claims 1, 29-30, 32, 34-38, and 40-45 are rejected under 35 U.S.C. 103 as being unpatentable over McIntosh (WO 99/47163) in view of Larsson (US 2016/0030489 A1).
McIntosh’s general disclosure relates to “to the field of preventing, reducing or treating an immune response caused by immune effector cells to foreign tissue and/or cells and/or organs. The invention further relates to preventing, reducing or treating transplant rejection and/or graft versus host reaction” (see abstract & page 1, lines 18-22, & page 2, lines 26-30).
McIntosh teaches that “mesenchymal stem cells are used to suppress or ameliorate an immune response to a transplant (tissue, organ, cells, etc.) by administering to the transplant recipient mesenchymal stem cells in an amount effective to suppress or ameliorate an immune response
against the transplant. The mesenchymal stem cells may be autologous to the transplant recipient or may be allogeneic to the transplant recipient” (see page 3, lines 29-35).
Regarding claims 30 and 34, McIntosh teaches the mesenchymal stem cells can be administered to the recipient before or at the same time as the transplant or subsequent to the transplant. The mesenchymal stem cells may be autologous or may be allogeneic to the recipient
and can be obtained from the donor (see page 4, lines 4-8) and the mesenchymal stem cells can also be administered to the recipient as part of the transplant such as ex vivo (see pages 4-5, lines 24-30)
Regarding claim 32, McIntosh teaches “donor tissue, organs or cells to be transplanted is the transplant. As examples of transplants may be included skin, bone marrow, and solid organs such as heart, pancreas, kidney, lung and liver” (see pages 7-8, bridging ¶).
Regarding claims 35-37, McIntosh teaches further comprising administering to the recipient immunosuppressive agents (see page 40, lines 25-26).
Regarding claim 38, McIntosh teaches multiple administrations of mesenchymal stem cells may be employed (see page 13, lines 5-6) and further teaches “the dosage of the mesenchymal stem cells varies within wide limits and will, of course be fitted to the individual requirements in each particular case. In general, in the case of parenteral administration, it is customary to administer from about 0.01 to about 5 million cells per kilogram of recipient body weight. The number of cells used will depend on the weight and condition of the recipient, the number of or frequency of administrations, and other variables known to those of skill in the art. The mesenchymal stem cells can be administered by a route which is suitable for the tissue, organ or cells to be transplanted. They can be administered systemically, i.e., parenterally, by intravenous injection” (see page 13, lines 20-35).
Regarding claim 40, McIntosh teaches the mesenchymal stem cells can be isolated and stored frozen until needed. The mesenchymal stem cells may also be culture-expanded to desired amounts and stored until needed (see page 6, lines 1-4).
However, McIntosh does not teach: term amniotic fluid (TAF) mesenchymal stem cells (MSCs) (claims 1 and 29’s limitation); or the cell characteristics such as seen in claims 41-45.
Larsson’s general disclosure relates to obtaining biological material, including amniotic
fluid and cells, including at birth, and in some aspects relates to safe, high-yield collection of sterile amniotic fluid and devices and methods for the same (see abstract & ¶ [0002]-[0010]). Larsson teaches amniotic fluid was collected from a healthy pregnant woman during full term caesarean delivery where “For isolation of cells, the 400 mL amniotic fluid was filtered through a 100-micron nylon mesh to separate the vernix and larger tissue debris aggregates. The filtered material was then put onto a Ficoll 400 sucrose gradient and centrifuged at room temperature for
5 minutes at 500 g” (see ¶ [0128]-[0134]: Example 3 which is a similar process to the instant specification at Figure 1 and although Larsson is silent with regards to the claimed cell characteristics, since both use similar process to obtain the cells, this is technical reasoning to believe that Larsson’s cell population will inherently have the same characteristics as in the claims).
It would have been obvious to one of ordinary skill in the art to employ or use the cell isolation method for obtaining mesenchymal stem cells such as taught by Larsson in the method of McIntosh. Note that McIntosh discloses “Although the invention is not limited thereof, mesenchymal stem cells can be isolated, preferably from bone marrow, purified, and expanded in culture, i.e. in vitro, to obtain sufficient numbers of cells for use in the methods described herein.
Mesenchymal stem cells, the formative pluripotent blast cells found in the bone, are normally present at very low frequencies in bone marrow (1: 100,000) and other mesenchymal tissues”
(see McIntosh at page 14, lines 6-11). Therefore, the ordinary artisan would have been motivated to use Larsson’s collection method because Larsson teaches a safe and high-yield collection method of sterile amniotic fluid cells. Thus, it would have been deemed to be a simple substitution using Larsson’s TAF-MSCs populations in McIntosh’s method for treating a transplant rejection. The ordinary artisan would have had a reasonable expectation of success is because both of the cited references are directed to mesenchymal stem cells.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 25, 28-30, and 40-45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 28, and 35-40 (claim set as filed on 09/18/2023) of co-pending Application no. 18/551,061. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding claims 1, 25, and 29-30, co-pending ‘061 teaches a method for prolonging the ex vivo life of a donor tissue/organ, comprising providing an ex vivo donor tissue/organ and contacting with isolated term amniotic fluid (TAF) mesenchymal stem cells (MSCs) (see claim 1). Although the instant claims and the co-pending claims differ in language with respect to the intended effect of the preambles, the co-pending claims should inherently perform the instant claims’ effect of modulating an immune response or treat transplant rejection because TAF MSCs have anti-inflammatory properties (as evident by the prior arts above).
Regarding claim 28, co-pending ‘061 teaches the donor organ is selected from lung, kidney, neural, skin, liver, heart, heart valve, trachea, pancreas, intestine, or colon (see claim 28).
Regarding claim 40, co-pending ‘061 teaches the TAF MSCs are clonal population, mixture, heterogeneous/homogenous, single-cell/pelleted, capable of CFU, functionally characterized, pre-sorted, passaged, and/or in frozen state (see claim 35).
Regarding claims 41-45, co-pending ‘061 teaches the isolated TAF MSCs comprise at least one surface marker; diameter between 15-25 µm, lower actin or vesicle expression, or the TAF MSCs are 10-99% lung, kidney, neural, skin, or neonatal (see claims 36-40).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims were allowed.
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/NGHI V NGUYEN/Primary Examiner, Art Unit 1653