DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendment filed July 16, 2025, has been received and entered.
Claims 1-20 are pending and examined on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date as follows:
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. 61/060,084, 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 one or more claims of this application.
With respect to claim 1 and its dependent claims 2-8, the prior-filed application 61/060,084 does not provide support or enablement for the method of claim 1 wherein the T cell population comprises cytotoxic T cells such that cytotoxic T cells are expanded and at least one surface molecule on the cytotoxic T cells is fucosylated. Therefore, claims 1-8 have the effective filing date of June 9, 2009 (filing date of PCT/US09/46800).
With respect to claim 9 and its dependent claims 10-16, the prior-filed application 61/060,084 does not provide support or enablement for the method of claim 9 wherein the T cell population comprises regulatory T cells such that regulatory T cells are expanded and at least one surface molecule on the regulatory T cells is fucosylated. Therefore, claims 9-16 have the effective filing date of June 9, 2009 (filing date of PCT/US09/46800).
With respect to claim 17 and its dependent claims 18-20, the prior-filed application 61/060,084 does not provide support or enablement for the method of claim 17 wherein a population of cells (specifically, population of T cells) is fucosylated ex vivo by contact with an α1,3-fucosyltransferase that fucosylated at least one surface molecule on the T cells to enhance selectin mediated binding thereof. Therefore, claims 17-20 have the effective filing date of June 9, 2009 (filing date of PCT/US09/46800).
Notice Re: Prior Art Available Under Both Pre-AIA and AIA
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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 1-4, 17, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Sackstein `383 (US 2008/0044383. Previously cited) in view of Sackstein 2008 (Nature Med. 2008. 14(2): 181-187. Previously cited) and Berenson (US 2003/0119185. Previously cited).
Sackstein `383 discloses methods and compositions for modifying glycans, e.g., glycans expressed on the surface of live cells or cell particles (abstract), the methods being an ex vivo method comprising contacting a population of cells with one or more glycosyltransferase compositions (paragraph [0043]; claim 16 of Sackstein `383). Sackstein `383 further teaches administering the treated cells to a patient in need thereof, including treating or alleviating a symptom of an immune disorder, tissue injury, or cancer (paragraphs [0018]-[0020] and [0041]-[0050], particularly paragraphs [0020] and [0048]-[0050]). The methods of Sackstein `383 are useful for increasing the in vivo engraftment/homing potential of the cells when administered to a subject (paragraph [0018]). Therefore, when the treated cells are administered to a subject for treating or alleviating a symptom of an immune disorder, tissue injury, or cancer, the methods of Sackstein `383 meet limitations of the claimed invention in that they are directed to a method of enhancing homing and engraftment of one or more cells in a patient in need of a treatment.
In various embodiments, the glycosyltransferase is a fucosyltransferase such as an alpha 1,3-fucosyltransferase (paragraph [0009]). Additionally, Sackstein `383 teaches that the composition used for modifying glycans may include one or more additional agents such as a donor substrate (e.g., a sugar) (paragraph [0010]). Donor substrates include fucose (paragraph [0010]). In particular, when the glycosyltransferase is a fucosyltransferase, the donor (donor substrate) is GDP-fucose (paragraph [0037]), i.e. guanosine diphosphate fucose as defined in paragraph [0060]. Therefore, when practicing the embodiment of Sackstein `383 in which the glycosyltransferase is an alpha 1,3-fucosyltransferase, it would have been obvious to the skilled artisan to have further included GDP-fucose (directed to the claimed ‘fucose carrier,’ specifically the ‘fucose carrier’ of instant claim 4) in the composition for modifying glycans used for practicing the method of Sackstein `383.
After modification, the cell or cell particle binds E-selectin and/or L-selectin (paragraph [0017]. Therefore, the ex vivo contact of a population of cells with the composition comprising an alpha 1,3-fucosyltransferase and GDP-fucose is directed to fucosylating at least one surface molecule on cells to enhance selectin mediated binding thereof, thereby meeting limitations of step (iii) of instant claim 1.
The method is performed on any cell in which cell surface glycan modification is desired (paragraph [0045]). Examples of such cells include T-lymphocytes (paragraph [0045]). As such, Sackstein `383 reasonably teaches performing their ex vivo method on 1) a T cell population; and 2) a heterogeneous population of T cells. Therefore, it would have been obvious to have performed any embodiment of the Sackstein `383 method on a T cell population (including a heterogeneous population of T cells), including the embodiment in which the glycan-modifying composition comprises an α1,3-fucosyltransferase and a fucose, e.g. GDP-fucose (directed to the claimed ‘fucose carrier’). It would have been within the purview of the skilled artisan to have applied any combination of the teachings of Sackstein `383 for the predictable result of modifying the glycans on the surface of T cells of a T cell population (including a heterogenous population of T cells).
In sum, Sackstein `383 meets limitations of the claimed invention since Sackstein `383 renders obvious a method of enhancing homing and engraftment of one or more T cells in a patient in need of treatment, the method comprising the steps of contacting a T cell population with an α1,3-fucosyltransferase and a fucose, e.g. GDP-fucose (directed to a ‘fucose carrier’) ex vivo to fucosylate at least one surface molecule on the T cell to enhance selectin mediated binding thereof (meeting limitations of step (iii) of instant claim 1); and administering the T cell population to the patient (meeting limitations of step (v) of instant claim 1).
Sackstein `383 differs from the claimed invention (instant claim 1 and its dependent claims) in that Sackstein `383 does not expressly disclose:
The T cell population comprises cytotoxic T cells, such that the step of contacting the T cell population with an α1,3-fucosyltrasnferase and a fucose, e.g. GDP-fucose (directed to a ‘fucose carrier’) specifically fucosylates at least one surface molecule on the cytotoxic T cells to enhance selectin mediated binding thereof;
before practicing the method of Sackstein `383, first isolating the T cell population (comprising cytotoxic T cells) from a blood sample from the patient having a medical condition amenable to cell therapy (an immune disorder, tissue injury or cancer, see paragraph [0020], for example), and expanding the cytotoxic T cells present in the T cell population ex vivo (i.e. steps (i) and (ii) of instant claim 1); and
combining the fucosylated, expanded cytotoxic T cells with a pharmaceutically-acceptable carrier to provide a pharmaceutical composition capable of administration to the patient; and the step of administering the T cell population to the patient comprises administering said pharmaceutical composition to the patient via a route selected from a group comprising intravenously, intraarterially, intramuscularly, subcutaneously, transdermally, intratracheally, intraperitoneally, intravitreally, and combinations thereof (i.e. step (iv) and further limitations of step (v) of instant claim 1).
Regarding difference (a) (Sackstein `383 does not disclose that the T cell population comprises cytotoxic T cells, such that the step of contacting the T cell population with an α1,3-fucosyltrasnferase and a fucose (e.g. GDP-fucose) specifically fucosylates at least one surface molecule on the cytotoxic T cells to enhance selectin mediated binding thereof):
Sackstein 2008 teaches a similar method of improving cell homing and engraftment using α1,3-fucosyltransferases (abstract).
More particularly, Sackstein 2008 teaches:
Beyond the implications for tissue regeneration, our results also provide a roadmap for testing how augmented E-selectin ligand activity on other pertinent cells (for example, regulatory T cells or cytotoxic T cells) could be harnessed to promote cell migration in adoptive cell therapeutics for a variety of physiologic and pathologic processes, including immune diseases, infectious diseases and cancer, all of which are accompanied by upregulated E-selectin expression in affected endothelial beds. (Page 185, second column).
As such, Sackstein `383 and Sackstein 2008, taken together, provide a clear teaching, suggestion, and motivation to contact cytotoxic T cells or a heterogeneous population of T cells that comprises cytotoxic T cells with an α1,3-fucosyltransferase in order to advantageously enhance the homing and engraftment of the cytotoxic T cells for therapeutic applications with a reasonable expectation of success. Therefore, it would have been obvious to have practiced the method rendered obvious by Sackstein `383 (using a composition comprising an α1,3-fucosyltransferase and a fucose, e.g. GDP-fucose) on a T cell population comprising cytotoxic T cells (including a heterogenous population of T cells that comprises cytotoxic T cells) for the predictable result of modifying the glycans on the cytotoxic T cells.
Regarding difference (b) (Sackstein `383 does not disclose isolating the T cell population comprising cytotoxic T cells from a blood sample from the patient having a medical condition amenable to cell therapy, and expanding the cytotoxic T cells present in the T cell population ex vivo):
Berenson teaches populations of T cells can be readily expanded ex vivo for subsequent therapeutic applications (abstract; ¶¶ 0007-0011, 0093, 0122, 0161, and 0170). Ex vivo T-cell expansion can be performed by isolation of T-cells and subsequent stimulation (paragraph [0089]). Prior to expansion, a source of T-cells is obtained from a subject, wherein the “subject” is intended to include living organisms in which an immune response can be elicited (e.g., mammals) (paragraph [0090]). It is appreciated that the methods of Berenson may be utilized for autologous cell therapy simultaneously with the subject and donor (paragraph [0179]). Therefore, Berenson teaches isolating the T-cells from the patient that is being treated. In certain embodiments, T cells can be obtained from a unit of blood collected from a subject using any number of techniques known to the skilled artisan (paragraph [0090]). Berenson further teaches the expanded T cells are a heterogeneous population of T cells that comprises cytotoxic T cells (¶ 0116).
Before the effective filing date of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method rendered obvious by Sackstein `383 and Sackstein 2008 in view of Berenson (in particular, isolating the T cell population comprising cytotoxic T cells from a blood sample of the patient being treated for an immune disorder, tissue injury, or cancer, and expanding the T cells, including the cytotoxic T cells, in the T cell population ex vivo) in order to advantageously produce large populations of T cells, such as cytotoxic T cells, for therapeutic applications with a reasonable expectation of success.
Regarding difference (c) (Sackstein `383 does not disclose combining the fucosylated, expanded cytotoxic T cells with a pharmaceutically-acceptable carrier to provide a pharmaceutical composition capable of administration to the patient; and the step of administering the T cell population to the patient comprises administering said pharmaceutical composition to the patient via a route selected from a group comprising intravenously, intraarterially, intramuscularly, subcutaneously, transdermally, intratracheally, intraperitoneally, intravitreally, and combinations thereof):
Sackstein `383 teaches formulating the cells in a physiologically acceptable solution (¶¶ 0009, 0012-0013, 0015 and 0039). Therefore, before the effecting filing date of the claimed invention, when practicing the method rendered obvious by Sackstein `383, Sackstein 2008, and Berenson, it would have been obvious to the person of ordinary skill in the art to combine the fucosylated, expanded T cells (which comprise fucosylated, expanded cytotoxic T cells) with a pharmaceutically acceptable carrier. While Sackstein `383 does not expressly teach administering the fucosylated T cells by the recited routes of administration, the reference does teach administration of fucosylated mesenchymal stem cells (MSCs) by intravenous infusion (¶ 0033). Moreover, as discussed above, Sackstein `383 teaches the fucosylated cells are useful for various therapeutic applications such a treatment of diseases and disorders (¶¶ 0048-0050). As such, before the effective filing date of the claimed invention, it would have been obvious to formulate the fucosylated, expanded T cells (which included fucosylated, expanded cytotoxic T cells) rendered obvious by Sackstein `383 in view of Sackstein 2008 and Berenson for administration via various art-recognized means, e.g., intravenously, with a reasonable expectation of success in order to advantageously produce a therapeutic useful for human administration, when practicing the method rendered obvious by Sackstein `383, Sackstein 2008, and Berenson (see Sackstein `383 ¶¶ 0020 and 0039). In doing so, the pharmaceutical composition that is administered comprises fucosylated, expanded cytotoxic T cells and a pharmaceutically acceptable carrier (physiologically acceptable solution).
Therefore, Sackstein `383 in view of Sackstein 2008 and Berenson renders obvious instant claims 1 and 2.
Regarding instant claim 3, Sackstein `383 teaches various alpha 1,3 fucosyltransferase examples including alpha 1,3 fucosyltransferase III, alpha 1,3 fucosyltransferase IV, alpha 1,3 fucosyltransferase VII, and alpha 1,3 fucosyltransferase IX (paragraph [0009]). Therefore, in performing the invention rendered obvious by Sackstein `383 in view of Sackstein 2008 and Berenson, it would have been obvious to the person of ordinary skill in the art to select any of these α1,3-fucosyltransferases to serve as the α1,3-fucosyltransferase used in performing the invention for the predictable result of modifying the glycans on the cytotoxic T cells. Therefore, instant claim 3 is rendered obvious.
Regarding instant claim 4, before the effective filing date of the claimed invention, one of ordinary skill in the art would have been free to first mix GDP-fucose (i.e. guanosine diphosphate fucose) with the α1,3-fucosyltransferase prior to contacting the mixture with the T cell population with a reasonable expectation of success when practicing the method rendered obvious by Sackstein `383, Sackstein 2008, and Berenson. See In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); See also In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious). Therefore, instant claim 4 is rendered obvious.
Regarding instant claims 17, 19, and 20, in rendering obvious instant claims 1 and 2, then Sackstein `383 in view of Sackstein 2008 and Berenson also renders obvious the broader scope of instant claims 17, 19, and 20.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Sackstein `383, Sackstein 2008, and Berenson as applied to claims 1-4, 17, 19, and 20 above, and further in view of Frenette (WO 2005/017115. Previously cited).
As discussed above, Sackstein `383 in view of Sackstein 2008 and Berenson renders obvious claims 1-4, 17, 19, and 20. The references differ from claim 5 in that they do not expressly disclose that the step of contacting the T cell composition (comprising cytotoxic T cells) with α1,3-fucosyltransferase and a fucose, e.g. GDP-fucose (directed to the claimed ‘fucose carrier’) (step (iii)) is performed in the presence of manganese.
Frenette discloses providing a population of cord blood hematopoietic progenitor cells (HPCs) which have increased fucosylation of selectin ligands, thereby increasing homing and enhancing bone marrow engraftment (page 7, third paragraph). The method of making the population of cord blood HPCs which have an increased fucosylation comprises treating a population of cord blood HPCs with a fucosyltransferase under conditions whereby unfucosylated selectin ligands on such cells are fucosylated (page 8, last paragraph). In a preferred embodiment, the fucosyltransferase is an α1,3-fucosyltransferase (page 8, last paragraph).
Additionally, Frenette discloses suitable conditions for the fucosylation (page 9, first paragraph). Conditions further include the presence of cofactors for the fucosyltransferase such as manganese (page 9, first paragraph).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to have included manganese when treating the T cell population with the composition comprising an α1,3-fucosyltransferase and a fucose, e.g. GDP-fucose when practicing the method rendered obvious by Sackstein `383 in view of Sackstein 2008 and Berenson. One of ordinary skill in the art would have been motivated to do this because manganese is considered a cofactor for suitable conditions for effecting fucosylation by a fucosyltransferase, as disclosed in Frenette. There would have been a reasonable expectation of practicing the method rendered obvious by Sackstein `383, Sackstein 2008, and Berenson with this modification since Frenette teaches a similar method of increasing homing and engraftment of cells in which an α1,3-fucosyltransferase may be used for increasing fucosylation on a population of cells. Therefore, instant claim 5 is rendered obvious.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Sackstein `383, Sackstein 2008, and Berenson as applied to claims 1-4, 17, 19, and 20 above, and further in view of Schuler (US 2009/0226404. Previously cited).
As discussed above, Sackstein `383 in view of Sackstein 2008 and Berenson renders obvious claims 1-4, 17, 19, and 20. The references differ from claim 6 in that they do not expressly disclose that step (iv) (combining the fucosylated, expanded cytotoxic T cells with a pharmaceutically acceptable carrier) is performed in the presence of human serum albumin.
Schuler relates to T cells transiently transfected with RNA, and the use of the transfected T cells for immunotherapy, particularly in the treatment of tumors, pathogen infection, autoimmune disease, transplant rejection, and graft versus host disease (abstract). For therapeutic uses, the T cells are administered in any suitable manner, often with pharmaceutically acceptable carriers (paragraph [0095]). The term “pharmaceutically acceptable carrier” as used in Schuler encompasses any of the pharmaceutical carriers compatible with T cells, such as protein excipients including serum albumin such as a human serum albumin (HSA) (paragraph [0048]).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to have included human serum albumin as a pharmaceutically acceptable carrier when preparing the T cells (including fucosylated, expanded cytotoxic T cells) for administration after modifying their glycans when performing the method rendered obvious by Sackstein `383, Sackstein 2008, and Berenson. One of ordinary skill in the art would have been motivated to do this because human serum albumin is a known pharmaceutically acceptable carrier compatible with T cells that are administered for therapeutic use, which is the goal of the Sackstein `383 invention. Therefore, instant claim 6 is rendered obvious.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Sackstein `383, Sackstein 2008, and Berenson as applied to claims 1-4, 17, 19, and 20 above, and further in view of Bruserud (Expert Opin. Biol. Ther. 2001. 1(6): 1005-1016. Previously cited).
As discussed above, Sackstein `383 in view of Sackstein 2008 and Berenson renders obvious claims 1-4, 17, 19, and 20. The references differ from claim 7 in that they do not expressly disclose that their method is further defined as a method of treating or reducing the occurrence of acute myelogenous leukemia.
However, Sackstein `383 teaches that their compositions are useful for treating a variety of diseases and disorders including hematologic disorders such as anemia, neutropenia, thrombocytosis, myeloproliferative disorders or hematologic neoplasms and cancer such as leukemia (paragraph [0049]). Therefore, it is obvious that the method of Sackstein `383 in view of Sackstein 2008 and Berenson is a method of treating or reducing the occurrence of leukemia.
Bruserud discloses that T-cell targeting immunotherapy is considered a possible strategy in the treatment of acute myelogenous leukaemia (AML) (abstract). Allogenic stem cell transplantation (SCT) has been used for treating AML, wherein the antileukaemic effect of this treatment is mediated by antileukaemic immune reactivity mediated by graft T-lymphocytes (page 1006, left column, second paragraph). Additionally, ex vivo generated AML-DC (AML dendritic cells) may be used to induce or enhance leukaemia-specific reactivity, with one possible strategy being in vitro co-culture of AML-DC with autologous T-cells that later are used for in vivo therapy (page 1012, right column, first full paragraph).
Before the effective filing date of the claimed invention, it would have been obvious that the method of Sackstein `383 in view of Sackstein 2008 and Berenson is suitable for treating acute myelogenous leukemia. This would have been obvious since the method of Sackstein `383 in view of Sackstein 2008 and Berenson is suitable for treating leukemia and since the method of Sackstein `383 in view of Sackstein 2008 and Berenson comprises administering T cells to a patient, wherein T-cell targeting immunotherapy is recognized as a possible strategy for the treatment of acute myelogenous leukaemia in Bruserud. There would have been a reasonable expectation of treating acute myelogenous leukemia since Bruserud discloses that graft T-lymphocytes mediate antileukaemic immune reactivity for the treatment of acute myelogenous leukemia. Therefore, instant claim 7 is rendered obvious.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Sackstein `383, Sackstein 2008, and Berenson as applied to claims 1-4, 17, 19, and 20 above, and further in view of Eming (J. Invest. Dermatol. 2007. 127:514-525. Previously cited).
As discussed above, Sackstein `383 in view of Sackstein 2008 and Berenson renders obvious claims 1-4, 17, 19, and 20. The references differ from claim 8 in that they do not expressly disclose that in the administration step to the patient (step (v)), the composition (the population of fucosylated, expanded T cells, including fucosylated, expanded cytotoxic T cells, combined with a pharmaceutically acceptable carrier) is administered to a site of injury or proximal thereto.
However, before the effective filing date of the claimed invention, it would have been obvious to administer the fucosylated, expanded T cells (comprising fucosylated, expanded cytotoxic T cells) taught by Sackstein `383, Sackstein 2008, and Berenson to a site of injury or proximal thereto because Eming teaches “[d]uring the phase of tissue remodeling, when wound closure has been completed, and local infections are already overcome, cells of the adaptive immune response, in particular T cells constitute the most frequent leukocyte subset in human skin wounds” (page 517, paragraph bridging left and center columns). One of ordinary skill in the art would have been motivated to combine the teachings of Sackstein `383, Sackstein 2008, Berenson, and Eming in order to advantageously increase the amount of T cells at or proximal to a wound site to promote healing. Accordingly, instant claim 8 is prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention especially in the absence of evidence to the contrary.
Claims 9-13, 17, 18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Sackstein `383 (US 2008/0044383. Previously cited) in view of Sackstein `558 (US 2006/0210558. Previously cited) and Berenson (US 2003/0119185. Previously cited).
Sackstein `383 discloses methods and compositions for modifying glycans, e.g., glycans expressed on the surface of live cells or cell particles (abstract), the methods being an ex vivo method comprising contacting a population of cells with one or more glycosyltransferase compositions (paragraph [0043]; claim 16 of Sackstein `383). Sackstein `383 further teaches administering the treated cells to a patient in need thereof, including treating or alleviating a symptom of an immune disorder, tissue injury, or cancer (paragraphs [0018]-[0020] and [0041]-[0050], particularly paragraphs [0020] and [0048]-[0050]). The methods of Sackstein `383 are useful for increasing the in vivo engraftment/homing potential of the cells when administered to a subject (paragraph [0018]). Therefore, when the treated cells are administered to a subject for treating or alleviating a symptom of an immune disorder, tissue injury, or cancer, the methods of Sackstein `383 meet limitations of the claimed invention in that they are directed to a method of enhancing homing and engraftment of one or more cells in a patient in need of a treatment.
In various embodiments, the glycosyltransferase is a fucosyltransferase such as an alpha 1,3-fucosyltransferase (paragraph [0009]). Additionally, Sackstein `383 teaches that the composition used for modifying glycans may include one or more additional agents such as a donor substrate (e.g., a sugar) (paragraph [0010]). Donor substrates include fucose (paragraph [0010]). In particular, when the glycosyltransferase is a fucosyltransferase, the donor (donor substrate) is GDP-fucose (paragraph [0037]), i.e. guanosine diphosphate fucose as defined in paragraph [0060]. Therefore, when practicing the embodiment of Sackstein `383 in which the glycosyltransferase is an alpha 1,3-fucosyltransferase, it would have been obvious to the skilled artisan to have further included GDP-fucose (directed to the claimed ‘fucose carrier,’ specifically the ‘fucose carrier’ of instant claim 12) in the composition for modifying glycans used for practicing the method of Sackstein `383.
After modification, the cell or cell particle binds E-selectin and/or L-selectin (paragraph [0017]. Therefore, the ex vivo contact of a population of cells with the composition comprising an alpha 1,3-fucosyltransferase and GDP-fucose is directed to fucosylating at least one surface molecule on cells to enhance selectin mediated binding thereof, thereby meeting limitations of step (iii) of instant claim 9.
The method is performed on any cell in which cell surface glycan modification is desired (paragraph [0045]). Examples of such cells include T-lymphocytes such as a “regulatory” lymphocyte (CD4+/CD25+/FOXP3+) (paragraph [0045]). As such, Sackstein `383 reasonably teaches performing their ex vivo method on 1) a T cell population that comprises regulatory T cells; and 2) a heterogeneous population of T cells that comprises regulatory T cells.
For performing their method on a T cell population comprising regulatory T cells (including a heterogenous population of T cells), Sackstein `383 differs from the claimed invention in that Sackstein `383 does not expressly disclose that their glycan-modifying composition comprising an α1,3-fucosyltransferase and GDP-fucose is used such that the glycans are modified of the regulatory T cells in said T cell population (directed to fucosylation of at least one surface molecule on the regulatory T cells to enhance selectin mediated binding thereof).
However, Sackstein `558 discloses a method of increasing the affinity of a cell for a selectin, e.g. an E-selectin and/or L-selectin, by contacting the cell with one or more agents that increase cell surface expression or activity of a hematopoietic cell E-selectin/L-selectin ligand (HCELL) polypeptide, wherein said agent can be an alpha 1,3 fucosyltransferase (paragraph [0012]). In one experiment, Sackstein `558 discloses fucosylation of human primary bone marrow lymphocytes, myeloid, and erythroid cells (paragraph [0248]). In particular, this involved analyzing the effects of exogenous FTVI (i.e. alpha 1,3 fucosyltransferase VI) treatment on various subsets of primary human bone marrow cells (paragraph [0249]). The subsets included T cells, and it was found that FTVI caused an increase in the numbers of HECA-452-reactive T cells (paragraph [0250]). Additionally, Sackstein `558 discloses fucosylation of primary human mobilized peripheral blood lymphocytes (paragraph [0257]). In that experiment, mobilized peripheral blood cells were treated with FTVI, and it was determined that treatment with FTVI caused the percentage of HECA-452-reactive T cells in peripheral blood to increase (paragraph [0258]). In Sackstein `558, a hematopoietic cell E-selectin/L-selectin ligand (HCELL) can be identified by reactivity with the rat monoclonal antibody HECA452 (paragraphs [0005]-[0007]). Therefore, Sackstein `558 discloses fucosylating T cells which increases affinity of the cell to a selectin by contacting a population comprising T cells with an alpha 1,3-fucosyltransferase, e.g. FTVI (alpha 1,3-fucosyltransferase VI).
Before the effective filing date of the claimed invention, it would have been obvious to have performed any embodiment of the Sackstein `383 method on a T cell population comprising regulatory T cells (including a heterogeneous population of T cells comprising regulatory T cells), including the embodiment in which the glycan-modifying composition comprises an α1,3-fucosyltransferase and GDP-fucose (directed to a ‘fucose carrier’) for the predictable result of modifying the glycans of the T cells, including the regulatory T cells, in the T cell population. It would have been within the purview of the skilled artisan to have applied any combination of the teachings of Sackstein `383 for the predictable result of modifying the glycans on the surface of T cells (including regulatory T cells) of a T cell population comprising regulatory T cells. Moreover, the person of ordinary skill in the art would have been motivated to use the glycan-modifying composition comprising an α1,3-fucosyltransferase and GDP-fucose in the Sackstein `383 method performed on a T cell population comprising regulatory T cells since Sackstein `558 found that T cells can be fucosylated by contacting the T cells with an α1,3-fucosyltransferase (α1,3-fucosyltransferase VI) such that the affinity to E-selectin/L-selectin is increased. There would have been a reasonable expectation that an α1,3-fucosyltransferase (in combination with GDP-fucose) would have modified the glycans on regulatory T cells of the T cell population since Sackstein `558 demonstrated the T cells can be fucosylated when contacted with an α1,3-fucosyltransferase (α1,3-fucosyltransferase VI) and since Sackstein `383 discloses an α1,3-fucosyltransferase amongst compositions for modifying a glycan (paragraph [0009]).
In sum, Sackstein `383 in view of Sackstein `558 meets limitations of the claimed invention since Sackstein `383 in view of Sackstein `558 renders obvious a method of enhancing homing and engraftment of one or more T cells in a patient in need of treatment, the method comprising the steps of contacting a T cell population comprising regulatory T cells with an α1,3-fucosyltransferase and GDP-fucose (directed to the claimed ‘fucose carrier’) ex vivo to fucosylate at least one surface molecule on the regulatory T cells to enhance selectin mediated binding thereof (meeting limitations of step (iii) of instant claim 9); and administering the T cell population comprising fucosylated regulatory T cells to a patient (meeting limitations of step (v) of instant claim 9).
Sackstein `383 in view of Sackstein `558 differs from the claimed invention (instant claim 9 and its dependent claims) in that they do not expressly disclose:
before practicing the method of Sackstein `383 in view of Sackstein `558, first isolating the T cell population (comprising regulatory T cells) from a blood sample from the patient having a medical condition amenable to cell therapy (an immune disorder, tissue injury or cancer, see paragraph [0020] of Sackstein `383, for example), and expanding the regulatory T cells present in the T cell population ex vivo (i.e. steps (i) and (ii) of instant claim 9); and
combining the fucosylated, expanded regulatory T cells with a pharmaceutically-acceptable carrier to provide a pharmaceutical composition capable of administration to the patient; and the step of administering the T cell population to the patient comprises administering said pharmaceutical composition to the patient via a route selected from a group comprising intravenously, intraarterially, intramuscularly, subcutaneously, transdermally, intratracheally, intraperitoneally, intravitreally, and combinations thereof (i.e. step (iv) and further limitations of step (v) of instant claim 9).
Regarding difference (a) (Sackstein `383 in view of Sackstein `558 does not disclose isolating the T cell population (comprising regulatory T cells) from a blood sample from the patient having a medical condition amenable to cell therapy, and expanding the regulatory T cells present in the T cell population ex vivo):
Berenson teaches populations of T cells can be readily expanded ex vivo for subsequent therapeutic applications (abstract; ¶¶ 0007-0011, 0093, 0122, 0161, and 0170). Ex vivo T-cell expansion can be performed by isolation of T-cells and subsequent stimulation (paragraph [0089]). Prior to expansion, a source of T-cells is obtained from a subject, wherein the “subject” is intended to include living organisms in which an immune response can be elicited (e.g., mammals) (paragraph [0090]). It is appreciated that the methods of Berenson may be utilized for autologous cell therapy simultaneously with the subject and donor (paragraph [0179]). Therefore, Berenson teaches isolating the T-cells from the patient being treated. In certain embodiments, T cells can be obtained from a unit of blood collected from a subject using any number of techniques known to the skilled artisan (paragraph [0090]). Berenson further teaches the expanded T cells are a heterogeneous population of T cells that comprises regulatory T cells (¶ 0116).
Before the effective filing date of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method rendered obvious by Sackstein `383 and Sackstein `558 in view of Berenson (in particular, isolating the T cell population comprising regulatory T cells from a blood sample of the patient being treated for an immune disorder, tissue injury, or cancer, and expanding the T cells, including the regulatory T cells, ex vivo) in order to advantageously produce large populations of T cells, such as regulatory T cells, for therapeutic applications with a reasonable expectation of success.
Regarding difference (b) (Sackstein `383 in view of Sackstein `558 does not disclose combining the fucosylated, expanded regulatory T cells with a pharmaceutically-acceptable carrier to provide a pharmaceutical composition capable of administration to the patient; and the step of administering the T cell population to the patient comprises administering said pharmaceutical composition to the patient via a route selected from a group comprising intravenously, intraarterially, intramuscularly, subcutaneously, transdermally, intratracheally, intraperitoneally, intravitreally, and combinations thereof):
Sackstein `383 teaches formulating the cells in a physiologically acceptable solution. (¶¶ 0009, 0012-0013, 0015 and 0039). Therefore, when practicing the method rendered obvious by Sackstein `383 in view of Sackstein `558 and Berenson, it would have been obvious to combine the fucosylated, expanded T cells (which comprise fucosylated, expanded regulatory T cells) with a pharmaceutically acceptable carrier. While Sackstein `383 does not expressly teach administering the fucosylated T cells by the recited routes of administration, the reference does teach administration of fucosylated mesenchymal stem cells (MSCs) by intravenous infusion (¶ 0033). Moreover, as discussed above, Sackstein `383 teaches the fucosylated cells are useful for various therapeutic applications such a treatment of diseases and disorders (¶¶ 0048-0050). As such, before the effective filing date of the claimed invention, it would have been obvious to formulate the fucosylated T cells taught by Sackstein `383 for administration via various art-recognized means, e.g., intravenously, with a reasonable expectation of success in order to advantageously produce a therapeutic useful for human administration, when practicing the method rendered obvious by Sackstein `383, Sackstein `558, and Berenson (See Sackstein ¶¶ 0020 and 0039). In doing so, the pharmaceutical composition that is administered comprises fucosylated, expanded regulatory T cells and a pharmaceutically acceptable carrier (physiologically acceptable solution).
Therefore, Sackstein `383 in view of Sackstein `558 and Berenson renders obvious instant claims 9 and 10.
Regarding instant claim 11, Sackstein `383 teaches various alpha 1,3 fucosyltransferase examples including alpha 1,3 fucosyltransferase III, alpha 1,3 fucosyltransferase IV, alpha 1,3 fucosyltransferase VI, alpha 1,3 fucosyltransferase VII, and alpha 1,3 fucosyltransferase IX (paragraph [0009]). Therefore, in performing the invention rendered obvious by Sackstein `383 in view of Sackstein `558 and Berenson, it would have been obvious to the person of ordinary skill in the art to select any of these α1,3-fucosyltransferases to serve as the α1,3-fucosyltransferase used in performing the invention for the predictable result of modifying the glycans on the regulatory T cells. Therefore, instant claim 11 is rendered obvious.
Regarding instant claim 12, before the effective filing date of the claimed invention, one of ordinary skill in the art would have been free to first mix GDP-fucose (i.e. guanosine diphosphate fucose) with the α1,3-fucosyltransferase prior to contacting the mixture with the T cell population with a reasonable expectation of success when practicing the method rendered obvious by Sackstein `383, Sackstein `558, and Berenson. See In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); See also In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious). Therefore, instant claim 12 is rendered obvious.
Regarding instant claim 13, Sackstein `383 discloses that commercially available α1,3-fucosyltransferase VI (FTVI; abbreviation defined in paragraph [0056]) contains Mn++ and glycerol (paragraph [0032]). It would have been obvious to have performed the method of Sackstein `383 in view of Sackstein `558 and Berenson with any α1,3-fucosyltransferase, including the commercially available α1,3-fucosyltransferase VI comprising manganese (Mn++), as it still would have been expected to modify the glycans on the T cells as sought by Sackstein `383. Therefore, instant claim 13 is rendered obvious.
Regarding instant claims 17, 18, and 20, in rendering obvious instant claims 9 and 10, then Sackstein `383 in view of Sackstein `558 and Berenson also renders obvious the broader scope of instant claims 17, 18, and 20.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Sackstein `383, Sackstein `558, and Berenson as applied to claims 9-13, 17, 18, and 20 above, and further in view of Schuler (US 2009/0226404. Previously cited).
As discussed above, Sackstein `383 in view of Sackstein `558 and Berenson renders obvious claims 9-13, 17, 18, and 20. The references differ from claim 14 in that they do not expressly disclose that step (iv) (combining the fucosylated, expanded regulatory T cells with a pharmaceutically acceptable carrier) is performed in the presence of human serum albumin.
Schuler relates to T cells transiently transfected with RNA, and the use of the transfected T cells for immunotherapy, particularly in the treatment of tumors, pathogen infection, autoimmune disease, transplant rejection, and graft versus host disease (abstract). For therapeutic uses, the T cells are administered in any suitable manner, often with pharmaceutically acceptable carriers (paragraph [0095]). The term “pharmaceutically acceptable carrier” as used in Schuler encompasses any of the pharmaceutical carriers compatible with T cells, such as protein excipients including serum albumin such as a human serum albumin (HSA) (paragraph [0048]).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to have included human serum albumin as a pharmaceutically acceptable carrier when preparing the T cells (including fucosylated, expanded regulatory T cells) for administration after modifying their glycans when performing the method rendered obvious by Sackstein `383 in view of Sackstein `558 and Berenson. One of ordinary skill in the art would have been motivated to do this because human serum albumin is a known pharmaceutically acceptable carrier compatible with T cells that are administered for therapeutic use, which is the goal of the Sackstein `383 invention. Therefore, instant claim 14 is rendered obvious.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Sackstein `383, Sackstein `558, and Berenson as applied to claims 9-13, 17, 18, and 20 above, and further in view of Bruserud (Expert Opin. Biol. Ther. 2001. 1(6): 1005-1016. Previously cited).
As discussed above, Sackstein `383 in view of Sackstein `558 and Berenson renders obvious claims 9-13, 17, 18, and 20. The references differ from claim 15 in that they do not expressly disclose that their method is further defined as a method of treating or reducing the occurrence of acute myelogenous leukemia.
However, Sackstein `383 teaches that their compositions are useful for treating a variety of diseases and disorders including hematologic disorders such as anemia, neutropenia, thrombocytosis, myeloproliferative disorders or hematologic neoplasms and cancer such as leukemia (paragraph [0049]). Therefore, it is obvious that the method of Sackstein `383 in view of Sackstein `558 and Berenson is a method of treating or reducing the occurrence of leukemia.
Bruserud discloses that T-cell targeting immunotherapy is considered a possible strategy in the treatment of acute myelogenous leukaemia (AML) (abstract). Allogenic stem cell transplantation (SCT) has been used for treating AML, wherein the antileukaemic effect of this treatment is mediated by antileukaemic immune reactivity mediated by graft T-lymphocytes (page 1006, left column, second paragraph). Additionally, ex vivo generated AML-DC (AML dendritic cells) may be used to induce or enhance leukaemia-specific reactivity, with one possible strategy being in vitro co-culture of AML-DC with autologous T-cells that later are used for in vivo therapy (page 1012, right column, first full paragraph).
Before the effective filing date of the claimed invention, it would have been obvious that the method of Sackstein `383 in view of Sackstein `558 and Berenson is suitable for treating acute myelogenous leukemia. This would have been obvious since the method of Sackstein `383 in view of Sackstein `558 and Berenson is suitable for treating leukemia and since the method of Sackstein `383 in view of Sackstein `558 and Berenson comprises administering T cells to a patient, wherein T-cell targeting immunotherapy is recognized as a possible strategy for the treatment of acute myelogenous leukaemia in Bruserud. There would have been a reasonable expectation of treating acute myelogenous leukemia since Bruserud discloses that graft T-lymphocytes mediate antileukaemic immune reactivity for the treatment of acute myelogenous leukemia. Therefore, instant claim 15 is rendered obvious.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Sackstein `383, Sackstein `558, and Berenson as applied to claims 9-13, 17, 18, and 20 above, and further in view of Eming (J. Invest. Dermatol. 2007. 127:514-525. Previously cited).
As discussed above, Sackstein `383 in view of Sackstein `558 and Berenson renders obvious claims 9-13, 17, 18, and 20. The references differ from claim 16 in that they do not expressly disclose that in the administration step to the patient (step (v)), the composition (the population of fucosylated, expanded T cells, including fucosylated, expanded regulatory T cells, combined with a pharmaceutically acceptable carrier) is administered to a site of injury or proximal thereto.
However, before the effective filing date of the claimed invention, it would have been obvious to administer the fucosylated, expanded T cells (comprising fucosylated, expanded regulatory T cells) taught by Sackstein`383, Sackstein `558, and Berenson to a site of injury or proximal thereto because Eming teaches “[d]uring the phase of tissue remodeling, when wound closure has been completed, and local infections are already overcome, cells of the adaptive immune response, in particular T cells constitute the most frequent leukocyte subset in human skin wounds” (page 517, paragraph bridging left and center columns). One of ordinary skill in the art would have been motivated to combine the teachings of Sackstein `383, Sackstein `558, Berenson, and Eming in order to advantageously increase the amount of T cells at or proximal to a wound site to promote healing. Accordingly, instant claim 16 is prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention especially in the absence of evidence to the contrary.
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 conflicting claims are not identical, but at least one examined ap