DETAILED ACTION
Claims 74-93 are currently pending.
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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/4/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification ([329]-[404]) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 85 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 85, which depends from claim 74, recites the limitation “wherein the megakaryocytes are engineered to express a recombinant protein”. Said limitation encompasses any recombinant protein.
A review of the specification shows that Applicants have not provided sufficient description of the invention to support they were in possession of engineering megakaryocytes to express any recombinant protein, e.g., viral rep or cap proteins, recombinant Human Parkinson disease protein 7 (PARK7).
In the instant case the only references in the specification to megakaryocytes expressing recombinant proteins are directed to recombinant proteins which
promote or accelerate normal wound healing, reduce scarring, and/or reduce fibrosis, e.g., erythropoietin, VEGF antagonists including antibodies and antibody analogs, IGF-1, bFGF, TGFβ-3, G-CSF), GM-CSF, KGF, fibronectin, vitronectin, thrombospondin, laminin, tenasin ([0103], [0255], and [0267]).
A review of the specification shows that Applicants have not provided sufficient description of the invention to support they were in possession of engineering megakaryocytes to express any recombinant protein.
Accordingly, the claims are considered to lack sufficient written description and are properly rejected under 35 USC 112, first paragraph.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 84 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 84 recites the phrase “…altered levels of expression of genes involved in membrane lipid ratios, protein glycosylation patterns, stress-induced proteins, or 14-3-3ζ translocation.” The term “altered levels” in claim 84 is a relative term which renders the claim indefinite. The term “altered levels” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The specification makes one reference to ‘altered levels of expression’ at [0250]. The specification does not further disclose what the altered level of expression is compared to, i.e., is the altered level of expression in relation to megakaryocytes obtained from patients suffering from cancer or Alzheimer’s disease or muscular dystrophy, or hemophilia, for example, or is the altered level of expression in relation to megakaryocytes obtained from patients who are not suffering from said diseases. Is the altered level of expression in relation to megakaryocytes from patients of a particular age group, e.g., older than 18 years of age, for example.
Given the specification does not define what is meant by “altered levels of expression” or further define the standard of comparison, one of ordinary skill in the art would not understand the metes and bounds of the term.
35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 74-93 are currently pending.
It is noted; these claims have been analyzed for eligibility in accordance with their broadest reasonable interpretation.
The Examiner notes that, although claim 74 recites a composition comprising megakaryocytes, the claimed megakaryocytes have a knockout of β2-microglobulin and thus would lack expression of β2-microglobulin, which is markedly different from the natural counterpart (see Malara et al, Figure 3C; PTO-892). Thus, the claims qualify as eligible subject matter.
Claim Rejections - 35 U.S.C § 102/103
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.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claim(s) 74-79 are rejected under 35 U.S.C. 102((a)(1) and 102(a)(2) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Thomson et al (US 2007/0077654; IDS 12/4/2024) (“Thomson”), as evidenced by Yang et al., (Experimental Hematology 2021, vol 106, pages 31-39; PTO-892) (“Yang”) and BioLegend (Product Information, PE anti-human CD29 Antibody, 5 pages, retrieved from the internet; PTO-892) (“Biolegend”).
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Thomson is directed to in vitro culture of human embryonic stem cells that are induced to differentiate first into the hematopoietic lineage and then into megakaryocytes, thereafter the cells generate platelets (Abstract).
Regarding claims 74-76, Thomson, at [0031], teaches of differentiating CD34+ cells in the presence of thrombopoietin (TPO), interleukin 3 (IL3), interleukin 6 (IL6), FLT-3, and stem cell factor (SCF), all factors chosen to specifically promote megakaryocyte differentiation and proliferation. Thomson teaches subjecting the megakaryocytes to flow cytometry and finding the megakaryocytes were positive for CD31, CD41, CD42a, CD42b, CD61, CD38, CD45 (weak) and CD62P, but negative for CD34, CD117, beta-microglobulin (HLA class I beta subunit) and HLA-DR, and notes this phenotype profile is consistent with normal megakaryocytes ([0022], [0031]; claim 5).
The marker expression profile of Thomson overlaps with the phenotype profile of the instantly claimed cells and, although Thomson does not further comment on the percentage of cells having the analyzed phenotype (i.e., at least 70% or at least 85%), it is considered, absent evidence to the contrary, that all the cells analyzed by flow cytometry have the recited phenotype profile, i.e., 100%.
Further regarding claim 76 and the limitation the megakaryocytes are also CD29+ and CD61+, although Thomson teaches the cells are CD61+, Thomson does not further comment on the cells being CD29+, however, given many of the other markers show similar expression pattern and Thomson notes the phenotype profile is consistent with normal megakaryocytes, CD29 expression maybe an inherent property of the megakaryocytes taught by Thomson.
Yang further evidences that megakaryocytes express integrin β1 (VLA-β) (see Yang at The β1 integrins and ECM ligand, pages 32-33) and Biolegend indicates CD29 is synonymous with integrin β1 (page 1). Accordingly, Thomson renders instant claims unpatentable.
Further regarding claims 77-79, it is noted that claim 77 recites the limitation “wherein the plurality of cells is derived in vitro from pluripotent stem cells”, claim 78 recites the limitation “wherein the pluripotent stem cells are embryonic stem cells”, and claim 79 recites the limitation “wherein the pluripotent stem cells are induced pluripotent stem cells”.
These limitations are directed to the manner by which the claimed plurality of cells are produced, i.e., product-by-process limitations.
Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In the instant case, the method by which the megakaryocytes have been produced in vitro from pluripotent stem cells, embryonic stem cells or induced pluripotent stem cells does not impart any unique structural/chemical properties to the megakaryocytes. As such instant claims 77-79 do not further limit claim 74 and thus are included in the rejection of claim 74.
Accordingly, Thomson renders instant claims unpatentable.
Claim Rejections - 35 USC § 103
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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 80-82 and 84 are rejected under 35 U.S.C. 103 as being unpatentable over Thomson, as evidenced by Yang and BioLegend, as applied to claims 74-77 above, and further in view of Lu et al., (Cell Research (2011) 21:530-545; IDS 12/4/2024) (“Lu”) and Lu et al., (Cell Research (2011) 21:530-545, Supplementary Information, Figure S3; see PTO-892) (“Lu Supplementary”).
Thomson, as evidenced by Yang and BioLegend, is set forth above.
Regarding claims 80 and 84, it is noted that Thomson does not further teach analyzing expression of CD235A+ to determine if the composition essentially lacks CD235A+ erythroid cells, as recited in claim 80. However, Lu is directed to in vitro methods for generating platelets from human embryonic stem cells, wherein the differentiation process produces megakaryocytes that are positive for CD41a and CD42b (Figure 1) and during the 6 days of differentiation flow cytometry showed a rapid decrease in CD235A+ (glycophorin A+) cells (i.e., altered levels of protein glycosylation, claim 84), coupled with the dramatic increase in CD41a+ and CD42b+ cells (Figure 1C; page 533, left col, last paragraph to right col, first paragraph; Lu Supplementary, Figure S3B). hence, Lu has established it was known that differentiated megakaryocytes essentially lack CD235A+ erythroid cells.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that during the differentiation of megakaryocytes in Thomson’s method, the differentiated megakaryocytes essentially lack CD235A+ erythroid cells.
The person of ordinary skill in the art would have been motivated to conduct megakaryocyte differentiation for the appropriate time period to produce megakaryocytes that essentially lack CD235A+ erythroid cells, as taught by Lu, for the predictable result of successfully producing mature megakaryocytes, thus meeting the limitation of claims 80 and 84.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Thomson and Lu because each of these teachings are directed at in vitro methods of producing megakaryocytes.
Regarding claims 81-82 and the limitations that less than 0.1% of the cells express the stem cell markers OCT4, NANOG, TRA-1-60, TRA-1-81, SSEA3, SSEA4 or alkaline phosphatase (claim 81), and less than 0.1% of cells express SSEA4 or TRA-1-60 (clam 82), it is again noted that Thomson’s method of directed differentiation produces mature megakaryocytes, and Lu has disclosed that during in vitro differentiation to produce mature megakaryocytes, the megakaryocytes express mature markers.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that during the differentiation of megakaryocytes in Thomson’s method, the differentiated megakaryocytes would no longer express stem cell markers, thus meeting the limitations of claims 81-82.
The person of ordinary skill in the art would have been motivated to conduct megakaryocyte differentiation for the appropriate time period to produce megakaryocytes that lack stem cell markers for the predictable result of successfully producing mature megakaryocytes, thus meeting the limitation of claims 81-82.
Claim(s) 83 is rejected under 35 U.S.C. 103 as being unpatentable over Thomson, as evidenced by Yang and BioLegend, as applied to claims 74-77 above, and further in view of Zhang et al., (The Journal of Biological Chemistry, Vol. 271, No. 8, Issue of February 23, pp. 4266-4272, 1996; see PTO-892) (“Zhang”) and Moroff et al., (Transfusion Medicine Reviews, Vol 11, No. 1 (January), 1997: pp 15-26; see PTO-892) (“Moroff”).
The teaching of Thomson, as evidenced by Yang and BioLegend is set forth above.
Regarding claim 83 and the limitation the cells of the composition are mitotically inactivated, it is noted that although Thomson teaches mature megakaryocytes having a normal phenotype, Thomson does not further comment on the megakaryocytes being mitotically inactivated. However, Zhang teaches that megakaryocytes (platelet precursors) mature to a polyploid cell as a result of DNA replication in the absence of mitosis (endomitosis) (Abstract).
Therefore, given that Thomson teaches differentiation to mature megakaryocytes and further production of platelets, it is reasonable to consider Thomson’s megakaryocytes are mitotically inactivated and entered endomitosis to produce platelets, thus meeting the limitation of claim 83.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that during the differentiation of megakaryocytes in Thomson’s method, the differentiated megakaryocytes would enter endomitosis in order to shed platelets.
The person of ordinary skill in the art would have been motivated to conduct megakaryocyte differentiation for the appropriate time period to produce megakaryocytes that enter endomitosis for subsequent platelet shedding, thus meeting the limitation of claim 83.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Thomson and Zhang because each of these teachings are directed at megakaryocytes.
Additionally regarding claim 83, it is noted that Moroff teaches that irradiation of blood and cellular components (i.e., mitotically inactivated) is the only accepted methodology to prevent transfusion-associated graft-versus-host disease.
Therefore, given that Thomson teaches producing mature megakaryocytes for subsequent production of a platelet product for transfusion, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further subject the megakaryocytes to irradiation in order to reduce transfusion-associated graft-versus-host disease.
The person of ordinary skill in the art would have been motivated to subject the megakaryocytes to irradiation, as taught by Moroff, for the predictable result of reducing transfusion-associated graft-versus-host disease, thus meeting the limitation of claim 83.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Thomson and Moroff because each of these teachings are directed at blood components.
Claim(s) 85 is rejected under 35 U.S.C. 103 as being unpatentable over Thomson, as evidenced by Yang and BioLegend, as applied to claims 74-77 above, and further in view of Burstein et al., (Experimental Hematology 27 (1999) 110-116; see PTO-892) (“Burstein”).
The teaching of Thomson, as evidenced by Yang and BioLegend, is set forth above.
Regarding claim 85, it is noted that Thomson does not further teach the megakaryocytes are engineered to express a recombinant protein. However, Burstein is directed to expression of foreign proteins (recombinant) in human megakaryocytes and platelets noting that, due to the progress in the in vitro culture of human megakaryocytes (MKs), such capability enables investigation into the possibility of modifying platelet structure/function by genetically altering the MKs. Burstein specifically modified the megakaryocytes to express recombinant CD9 and reports that retrovirally mediated gene transfer is a viable approach for genetically altering MKs (left col, page 110).
Therefore, given that Thomson teaches in vitro production of mature megakaryocytes for subsequent production of a platelet product for transfusion and Burstein teaches that MKs can be genetically modified in order to modify platelet function, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to engineer the in vitro produced megakaryocytes for the predictable result of modifying/optimizing platelet function, thus meeting the limitation of claim 85.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Thomson and Burstein because each of these teachings are directed at megakaryocytes and platelets.
Claim(s) 86 is rejected under 35 U.S.C. 103 as being unpatentable over Thomson and Burstein, as evidenced by Yang and BioLegend, as applied to claim 85 above, and further in view of Kyriakides et al., (Blood 2003 May 15;101(10):3915-23; see PTO-892) (“Kyriakides”).
The teaching of Thomson and Burstein, as evidenced by Yang and BioLegend is set forth above.
Regarding claim 86, it is noted that Burstein teaches the recombinant protein is CD9. Burstein does not further teach the recombinant protein is one of those recited in claim 86, e.g. thrombospondin. However, Kyriakides teaches that when megakaryocytes (MKs) are cultured in vitro, MKs contain little thrombospondin-2 (TSP2) protein or mRNA, as compared to their bone marrow counterparts which express high levels of TSP2. Kyriakides teaches that lack of TSP2 compromises platelet aggregation ability (Abstract).
Therefore, given that Thomson teaches in vitro production of mature megakaryocytes for subsequent production of a platelet product for transfusion and Kyriakides teaches that when megakaryocytes (MKs) are cultured in vitro, MKs are deficient in TSP2 protein which results in platelets with compromised aggregation ability, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to engineer the in vitro produced megakaryocytes to express thrombospondin-2 (TSP2) for the predictable result of producing platelets that mimic native aggregation ability, thus meeting the limitation of claim 86.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Thomson and Kyriakides because each of these teachings are directed at megakaryocytes and platelets.
Claim(s) 87 and 88 are rejected under 35 U.S.C. 103 as being unpatentable over Thomson and Burstein, as evidenced by Yang and BioLegend, as applied to claim 85 above, and further in view of Ho-Tin-Noe et al., (Cancer Research 2009 Jul 7;69(14): 5623-5626; see PTO-892)(“Cancer Research”), Italiano et al., (Blood (2008) 111 (3):1227-1233; see PTO-892) (“Italiano”) and Lien, S., Lowman, H.B. (2008). Therapeutic Anti-VEGF Antibodies. In: Chernajovsky, Y., Nissim, A. (eds) Therapeutic Antibodies. Handbook of Experimental Pharmacology, vol 181. Springer, Berlin, Heidelberg, pages 132-150) (“Lien”).
The teaching of Thomson and Burstein, as evidenced by Yang and BioLegend is set forth above.
Regarding claims 87-88, it is noted that Burstein teaches the recombinant protein is CD9. Burstein does not further teach the recombinant protein is a vascular endothelial growth factor (VEGF) inhibitor (claim 87), specifically wherein the VEGF inhibitor is an antibody (claim 88). However, Cancer Research teaches that activated platelets are crucial regulators of tumor vascular homeostasis by preventing tumor hemorrhage and this effect relies on secretion of the platelet granule content. Cancer Research teaches that targeting platelet secretory activities may provide a new approach to destabilize tumor vasculature (Abstract). Cancer Research further teaches that platelets are a rich source of anti-angiogenic and pro-angiogenic factors that can be differentially released upon platelet activation (page 1, last paragraph).
Italiano, like Cancer Research, acknowledges that platelets play an important role in tumor growth and further assessed the release of angiogenesis stimulators (VEGF) and angiogenesis inhibitors (endostatin). Italiano confirmed segregation of the stimulators and inhibitors into separate and distinct α-granules. Italiano teaches that the separate packaging of angiogenesis regulators into pharmacologically and morphologically distinct populations of α-granules in megakaryocytes and platelets may provide a mechanism by which platelets can locally stimulate or inhibit angiogenesis.
Lien teaches of two recombinant humanized anti-VEGF antibodies, bevacizumab (Avastin anti-VEGF antibody) and ranibizumab (Lucentis anti-VEGF antibody), for treating tumor cancers, e.g., metastatic colorectal cancer, and having demonstrated therapeutic utility in blocking VEGF-induced angiogenesis (Abstract; 4.2 Clinical Studies with Bevacizumab, page 140).
Therefore, given that Thomson teaches production of mature megakaryocytes for subsequent production of a platelet product for transfusion and taking in hand that
Cancer Research teaches that targeting platelet secretory activities may provide a new approach to destabilize tumor vasculature and Italiano teaches that the separate packaging of angiogenesis regulators into pharmacologically and morphologically distinct populations of α-granules in megakaryocytes and platelets may provide a mechanism by which platelets can locally stimulate or inhibit angiogenesis, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to engineer the in vitro produced megakaryocytes to express recombinant humanized anti-VEGF antibodies, e.g., bevacizumab, for the predictable result of producing platelets that block VEGF-induced angiogenesis in tumors, thus meeting the limitations of claim 87-88.
The skilled artisan would have had a reasonable expectation of success in combining the above teachings because each of the teachings are directed at biological therapeutics.
Claim(s) 89-90 are rejected under 35 U.S.C. 103 as being unpatentable over Thomson, as evidenced by Yang and BioLegend, as applied to claims 74-77 above, and further in view of Tfayli et al, Medscape.org, 2008, retrieved from the internet; see PTO-892) (“Tfayli”) and Ivashkiv et al., (Trends Immunol. 2012 Dec 4;34(5):216-223; see PTO-892) (“Ivashkiv”).
The teaching of Thomson, as evidenced by Yang and BioLegend, is set forth above.
Regarding claims 89-90 and the limitations directed to the composition further comprises a BET inhibitor or a c-myc inhibitor (claim 89), and the composition comprises a BET inhibitor, wherein the BET inhibitor is GSK1210151A (I-BET 151) (claim 90), it is noted that Thomson does not further comment on the megakaryocyte composition further comprising said inhibitor.
Ivashkiv teaches that iBET and related compounds JQ1 and iBET151 strongly suppress Myc expression and also show great promise for the treatment of Myc-driven cancers such as acute myeloid leukemia (AML) and multiple myeloma (page 220, left col, first paragraph).
Tfayli discusses management of thrombocytopenia in patients with leukemia, e.g. acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and teaches that thrombocytopenia is very common at presentation in patients with acute leukemia (myelogenous and lymphocytic) and since these patients are usually treated with combination chemotherapy to induce remission, thrombocytopenia is essentially universal in these patients and can persist for several weeks until the healthy bone marrow recovers (Introduction, second paragraph). Tfayli teaches that platelet transfusion remains the most common intervention in the management of thrombocytopenia in patients with leukemia (Management, Platelet Transfusion, page 2).
Therefore, given that Ivashkiv teaches I-BET 151 is used for treating cancers such as ALL and AML, and knowing that such patients require platelet transfusions to manage thrombocytopenia that develops in said patients and Thomson teaches producing mature megakaryocytes for subsequent production of a platelet product for transfusion, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Thomson’s megakaryocytes with the BET inhibitor I-BET 151, as taught by Tfayli.
The person of ordinary skill in the art would have been motivated combine I-BET 151 with Thomson’s megakaryocytes for the predictable result of managing thrombocytopenia that develops in patients undergoing I-BET 151 cancer treatment, thus meeting the limitation of claims 89-90.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Thomson with Ivashkiv and Tfayli because these teachings are directed at treatments employed in leukemia.
Claim(s) 91-92 are rejected under 35 U.S.C. 103 as being unpatentable over Thomson, as evidenced by Yang and BioLegend, as applied to claims 74-77 above, and further in view of Lu et al., (Cell Res. 2011 Mar;21(3):530-45; IDS 12/4/2024) (“Lu”), as evidenced by Abcam (GM 6001, MMP inhibitor, Product Information, retrieved from the internet; see PTO-892) (“Abcam”).
The teaching of Thomson, as evidenced by Yang and BioLegend is set forth above.
Regarding claims 91-92, it is noted that Thomson does not further teach the megakaryocyte composition further comprising a MMP inhibitor (claim 91), or the MMP inhibitor is an MMP8-specific inhibitor (claim 92).
Lu, like Thomson, is directed to in vitro methods for generating functional megakaryocytes and platelets from human embryonic stem cells (Abstract). Lu teaches that the addition of the MMP inhibitor GM6001 (GM) improved differentiation of megakaryocytes to platelets expressing both CD41a and CD42b, as compared to very low expression of CD42b without the addition of the MMP inhibitor GM6001 (page 534, right col).
Abcam evidences that GM 6001 is an inhibitor of MMP-8.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include a MMP inhibitor, specifically a MMP-8 inhibitor, thus meeting the limitations of claims 91-92.
The person of ordinary skill in the art would have been motivated to include a MMP-8 inhibitor, as taught by Lu, for the predictable result of producing an increased population of megakaryocytes and platelets that retain expression of CD42b thus maintaining platelet integrity.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Thomson and Lu because each of these teachings are directed at in vitro production of megakaryocytes and platelets.
Claim(s) 93 is rejected under 35 U.S.C. 103 as being unpatentable over Thomson in view of Lu, as evidenced by Yang, BioLegend and Abcam, as applied to claims 91-92 above, and further in view of Gaggar et al., (J Immunol. 2008 Apr 15;180(8):5662–5669; see PTO-892) (“Gaggar”).
The teaching of Thomson in view of Lu, as evidenced by Yang, BioLegend and Abcam is set forth above.
Regarding claim 93, it is noted that the combined prior art does not further teach the MMP-8 inhibitor is (3R)-(+)-[2– 4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamate] (synonymous with M8I and MMP-8 inhibitor I).
Gaggar discusses the specific multistep proteolytic pathway involved in PGP (proline-glycine-proline) generation from collagen, involving matrix metalloprotease 8 (MMP8), matrix metalloprotease 9 (MMP9) and prolyl endopeptidase, a serine protease for which we identify a novel role in inflammation (Abstract). Table 1 of Gaggar shows that (3R)-(+)-[2– 4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamate] is a MMP-8 inhibitor, having an IC50 = 4 nM.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute (3R)-(+)-[2– 4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamate] for GM 6001 since both are known MMP-8 inhibitors. Therefore, one of ordinary skill in the art would recognize this as simply substituting one MMP-8 inhibitor for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Substitution of one element for another known in the field is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Claim(s) 74, 76-82, 84 and 91-92 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al., (Cell Research (2011) 21:530-545; IDS 12/4/2024) (“Lu”) and Lu et al., (Cell Research (2011) 21:530-545, Supplementary Information, Figure S3; see PTO-892) (“Lu Supplementary”), in view of Figueiredo et al (Transfusion. 2010 Aug;50(8):1690-701; IDS 12/4/2024) (“Figueiredo”), as evidenced by Yang et al., (Experimental Hematology 2021, vol 106, pages 31-39; PTO-892) (“Yang”), BioLegend (Product Information, PE anti-human CD29 Antibody, 5 pages, retrieved from the internet; PTO-892) (“Biolegend”) and Abcam (GM 6001, MMP inhibitor, Product Information, retrieved from the internet; see PTO-892) (“Abcam”).
Regarding claim 74, Lu teaches that success has been achieved in producing functional megakaryocytes (MKs) and platelets from CD34+ hematopoietic cells, however in vitro expansion has been limited (page 531, left col, second para). Lu further teaches that additional studies have provided proof of concept for in vitro production of MKs from human embryonic stem cells (hESCs), which are an unlimited source of megakaryocyte progenitors. Lu’s study is directed to an efficient method of generating functional MKs from hESCs on a large scale using hemangioblasts/blast cells (BCs) as intermediates (page 531, left col, last sentenced to right col, first paragraph).
Lu’s Figure 1 shows 79.2% (i.e., at least 70%) of the population of megakaryocytes produced from the CD34+ progenitors are positive for CD41a and CD42b by day 4 of differentiation, as recited in claim 74.
Lu further teaches that, using TSI medium resulted in achieving a fivefold increase in the number of CD41a+ MKs during a period of 6 days (Figure 1B). During this period, flow cytometry analysis showed a rapid decrease in CD235a+ (glycophorin A+) cells, coupled with a dramatic increase in CD41a+ and CD42b+ (GPIbα) cells. By day 4-6, ~90% of the cells expressed CD41a (Figure 1C; Supplementary information, Figure S3A), and 80% of the cells were also positive for CD42b (Figure 1C). In addition to CD42b, CD42a (GPIX) and CD61 (integrin β3 subunit) were also expressed on the surface of CD41a+ MKs (Supplementary information, Figure S3B).
Lu does not further teach knockout of endogenous β2 microglobulin-deficient, i.e., β2 microglobulin-deficient megakaryocytes. However, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used β2 microglobulin-deficient megakaryocytes to prepare β2 microglobulin-deficient platelets that have reduced immunogenicity. For example, Figueiredo reports on the generation of HLA-deficient platelets (PLTs) from hematopoietic progenitor cells (Title; Abstract). Figueiredo teaches that immune factors (such as the development of anti-HLA antibodies) are a major problem that leads to PLT refractoriness (page 1690, second col.). Figueiredo teaches it would be desirable to have PLT units in which the antigenicity of HLA Class I has been eliminated from the PLT surface (page 1690, right col.). Figueiredo teaches an RNAi-based approach to permanently silence (i.e., knockout) the expression of HLA Class I molecules on PLTs released from megakaryocytes derived from CD34+ progenitor cells and demonstrates that these HLA Class I–deficient PLTs are functionally equivalent to blood-derived PLTs, while featuring reduced immunogenicity (Results; Discussion; pgs. 1691-1700).
In view of Figueiredo’s teachings, it would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to use β2 microglobulin-deficient megakaryocytes, for the predicable result of providing platelets having reduced immunogenicity per Figueiredo.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lu and Figueiredo because each of these teachings are directed at therapeutic uses of platelets derived in vitro from megakaryocytes.
Regarding claim 76 it is noted that Lu teaches the megakaryocytes have positive expression of CD61 (page 533, right col; Supplementary information, Figure S3B). Lu does not further comment on the cells being CD29+, however, given many of the other markers show similar expression pattern CD29 expression maybe an inherent property of the megakaryocytes taught by Lu.
Yang further evidences that megakaryocytes express integrin β1 (VLA-β) (see Yang at The β1 integrins and ECM ligand, pages 32-33) and Biolegend indicates CD29 is synonymous with integrin β1 (page 1).
Accordingly, Lu, in view of Figueiredo renders instant claims unpatentable.
Regarding claims 77-79, as discussed above it is noted that claim 77 recites the limitation “wherein the plurality of cells is derived in vitro from pluripotent stem cells”, claim 78 recites the limitation “wherein the pluripotent stem cells are embryonic stem cells”, and claim 79 recites the limitation “wherein the pluripotent stem cells are induced pluripotent stem cells”.
These limitations are directed to the manner by which the claimed plurality of cells are produced, i.e., product-by-process limitations.
Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In the instant case, the method by which the megakaryocytes have been produced in vitro from pluripotent stem cells, embryonic stem cells or induced pluripotent stem cells does not impart any unique structural/chemical properties to the megakaryocytes. As such instant claims 77-79 do not further limit claim 74 and thus are included in the rejection of claim 74.
Regarding claims 80 and 84, Lu teaches the differentiation process produces megakaryocytes that are positive for CD41a and CD42b (Figure 1) and during the 6 days of differentiation flow cytometry showed a rapid decrease in CD235A+ (glycophorin A+) cells (i.e., altered levels of protein glycosylation, claim 84), coupled with the dramatic increase in CD41a+ and CD42b+ cells (Figure 1C; page 533, left col, last paragraph to right col, first paragraph; Lu Supplementary, Figure S3B). Hence, Lu has established it was known that differentiated megakaryocytes essentially lack CD235A+ erythroid cells, thus meeting the limitations of claims 80 and 84.
Regarding claims 81-82 and the limitations that less than 0.1% of the cells express the stem cell markers OCT4, NANOG, TRA-1-60, TRA-1-81, SSEA3, SSEA4 or alkaline phosphatase (claim 81), and less than 0.1% of cells express SSEA4 or TRA-1-60 (clam 82), it is noted that Lu’s method of directed differentiation produces mature megakaryocytes, and Lu has disclosed that during in vitro differentiation to produce mature megakaryocytes, the megakaryocytes express mature markers.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that during the differentiation of megakaryocytes in Lu’s method, the differentiated megakaryocytes would no longer express stem cell markers, thus meeting the limitations of claims 81-82.
The person of ordinary skill in the art would have been motivated to conduct megakaryocyte differentiation for the appropriate time period to produce megakaryocytes that lack stem cell markers for the predictable result of successfully producing mature megakaryocytes, thus meeting the limitation of claims 81-82.
Regarding claims 91-92, Lu teaches that the addition of the MMP inhibitor GM6001 (GM) improved differentiation of megakaryocytes to platelets expressing both CD41a and CD42b, as compared to very low expression of CD42b without the addition of the MMP inhibitor GM6001 (page 534, right col). Abcam evidences that GM 6001 is an inhibitor of MMP-8. Thus, Lu’s teaching meets the limitations of claims 91-92.
Claim 75 is rejected under 35 U.S.C. 103 as being unpatentable over Lu, in view of Figueiredo, as evidenced by Yang, BioLegend and Abcam, as applied to claims 74, 76-82, 84 and 91-92 above, and further in view of Tomer et al., (Blood, Vol 70, No 6 (December), 1987: pp 1735-1742; see PTO-892) (“Tomer”).
The teaching of Lu, in view of Figueiredo, as evidenced by Yang, BioLegend and Abcam is set forth above.
Regarding claim 75, although Lu teaches 80% of the cells were positive for both CD41a and CD42b (Figure 1C), Lu does not further comment on at least 85% of the cells are positive for both CD41a and CD42b. However, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare purified populations (i.e., at least 85% of the megakaryocytes are CD41a+ and CD42b+) of the in vitro produced megakaryocytes. For example, Tomer is directed to methods for purifying megakaryocyte populations to achieve homogeneity by selective fluorescence sorting based on lineage markers (Abstract). Tomer teaches that purity was further enhanced by aborting negative events coinciding with positive events (Flow cytometry, right col, page 1736). Tomer teaches that after sorting and staining with hematoxylin, the cells appeared to be morphologically pure megakaryocytes (Fig 3), thus providing purified viable human megakaryocytes that are required for the study of some aspects of the biology of the cells (Discussion, right col, page 1739).
The person of ordinary skill in the art would have been motivated to conduct cell sorting to remove undesirable/immature cell populations to obtain a homogenous population of megakaryocytes that are positive for both CD41a and CD42b for the predictable result of successfully producing a megakaryocyte population that would subsequently produce CD41a+ and CD42b+ platelets.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lu and Tomer because each of these teachings are directed at production of megakaryocytes and platelets.
Claim 83 is rejected under 35 U.S.C. 103 as being unpatentable over Lu, in view of Figueiredo, as evidenced by Yang, BioLegend and Abcam, as applied to claims 74, 76-82, 84 and 91-92 above, and further in view of Zhang et al., (The Journal of Biological Chemistry, Vol. 271, No. 8, Issue of February 23, pp. 4266-4272, 1996; see PTO-892) (“Zhang”) and Moroff et al., (Transfusion Medicine Reviews, Vol 11, No. 1 (January), 1997: pp 15-26; see PTO-892) (“Moroff”).
The teaching of Lu, in view of Figueiredo, as evidenced by Yang, BioLegend and Abcam is set forth above.
Regarding claim 83 and the limitation the cells of the composition are mitotically inactivated, it is noted that although Lu teaches producing mature megakaryocytes, Lu does not further comment on the megakaryocytes being mitotically inactivated. However, Zhang teaches that megakaryocytes (platelet precursors) mature to a polyploid cell as a result of DNA replication in the absence of mitosis (endomitosis) (Abstract).
Therefore, given that Lu teaches differentiation to mature megakaryocytes and further production of platelets, it is reasonable to consider Lu’s megakaryocytes are mitotically inactivated and entered endomitosis to produce platelets, thus meeting the limitation of claim 83.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that during the differentiation of megakaryocytes in Lu’s method, the differentiated megakaryocytes would enter endomitosis in order to shed platelets.
The person of ordinary skill in the art would have been motivated to conduct megakaryocyte differentiation for the appropriate time period to produce megakaryocytes that enter endomitosis for subsequent platelet shedding, thus meeting the limitation of claim 83.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lu and Zhang because each of these teachings are directed at megakaryocytes.
Additionally, regarding claim 83, it is noted that Moroff teaches that irradiation of blood and cellular components (i.e., mitotically inactivated) is the only accepted methodology to prevent transfusion-associated graft-versus-host disease.
Therefore, given that Lu teaches producing mature megakaryocytes for subsequent production of a platelet product for transfusion, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further subject the megakaryocytes to irradiation in order to reduce transfusion-associated graft-versus-host disease.
The person of ordinary skill in the art would have been motivated to subject the megakaryocytes to irradiation, as taught by Moroff, for the predictable result of reducing transfusion-associated graft-versus-host disease, thus meeting the limitation of claim 83.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lu and Moroff because each of these teachings are directed at blood components.
Claim 85 is rejected under 35 U.S.C. 103 as being unpatentable over Lu, in view of Figueiredo, as evidenced by Yang, BioLegend and Abcam, as applied to claims 74, 76-82, 84 and 91-92 above, and further in view of Burstein et al., (Experimental Hematology 27 (1999) 110-116; see PTO-892) (“Burstein”).
The teaching of Lu, in view of Figueiredo, as evidenced by Yang, BioLegend and Abcam is set forth above.
Regarding claim 85, it is noted that Lu does not further teach the megakaryocytes are engineered to express a recombinant protein. However, Burstein is directed to expression of foreign proteins (recombinant) in human megakaryocytes and platelets noting that, due to the progress in the in vitro culture of human megakaryocytes (MKs), such capability enables investigation into the possibility of modifying platelet structure/function by genetically altering the MKs. Burstein specifically modified the megakaryocytes to express recombinant CD9 and reports that retrovirally mediated gene transfer is a viable approach for genetically altering MKs (left col, page 110).
Therefore, given that Lu teaches in vitro production of mature megakaryocytes for subsequent production of a platelet product for transfusion and Burstein teaches that MKs can be genetically modified in order to modify platelet function, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to engineer the in vitro produced megakaryocytes for the predictable result of modifying/optimizing platelet function, thus meeting the limitation of claim 85.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lu and Burstein because each of these teachings are directed at megakaryocytes and platelets.
Claim(s) 86 is rejected under 35 U.S.C. 103 as being unpatentable over Lu, in view of Figueiredo and Burstein, as evidenced by Yang, BioLegend and Abcam, as applied to claim 85 above, and further in view of Kyriakides et al., (Blood 2003 May 15;101(10):3915-23; see PTO-892) (“Kyriakides”).
The teaching of Lu, in view of Figueiredo, as evidenced by Yang, BioLegend and Abcam is set forth above.
Regarding claim 86, it is noted that Burstein teaches the recombinant protein is CD9. Burstein does not further teach the recombinant protein is one of those recited in claim 86, e.g. thrombospondin. However, Kyriakides teaches that when megakaryocytes (MKs) are cultured in vitro, MKs contain little thrombospondin-2 (TSP2) protein or mRNA, as compared to their bone marrow counterparts which express high levels of TSP2. Kyriakides teaches that lack of TSP2 compromises platelet aggregation ability (Abstract).
Therefore, given that Lu teaches in vitro production of mature megakaryocytes for subsequent production of a platelet product for transfusion and Kyriakides teaches that when megakaryocytes (MKs) are cultured in vitro, MKs are deficient in TSP2 protein which results in platelets with compromised aggregation ability, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to engineer the in vitro produced megakaryocytes to express thrombospondin-2 (TSP2) for the predictable result of producing platelets that mimic native aggregation ability, thus meeting the limitation of claim 86.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lu and Kyriakides because each of these teachings are directed at megakaryocytes and platelets.
Claim(s) 87 and 88 are rejected under 35 U.S.C. 103 as being unpatentable over Lu, in view of Figueiredo and Burstein, as evidenced by Yang, BioLegend and Abcam, as applied to claim 85 above, and further in view of Ho-Tin-Noe et al., (Cancer Research 2009 Jul 7;69(14): 5623-5626; see PTO-892)(“Cancer Research”), Italiano et al., (Blood (2008) 111 (3):1227-1233; see PTO-892) (“Italiano”) and Lien, S., Lowman, H.B. (2008). Therapeutic Anti-VEGF Antibodies. In: Chernajovsky, Y., Nissim, A. (eds) Therapeutic Antibodies. Handbook of Experimental Pharmacology, vol 181. Springer, Berlin, Heidelberg, pages 132-150; see PTO-892) (“Lien”).
The teaching of Lu, in view of Figueiredo and Burstein, as evidenced by Yang, BioLegend and Abcam is set forth above.
Regarding claims 87-88, it is noted that Burstein teaches the recombinant protein is CD9. Burstein does not further teach the recombinant protein is a vascular endothelial growth factor (VEGF) inhibitor (claim 87), specifically wherein the VEGF inhibitor is an antibody (claim 88). However, Cancer Research teaches that activated platelets are crucial regulators of tumor vascular homeostasis by preventing tumor hemorrhage and this effect relies on secretion of the platelet granule content. Cancer Research teaches that targeting platelet secretory activities may provide a new approach to destabilize tumor vasculature (Abstract). Cancer Research further teaches that platelets are a rich source of anti-angiogenic and pro-angiogenic factors that can be differentially released upon platelet activation (page 1, last paragraph).
Italiano, like Cancer Research, acknowledges that platelets play an important role in tumor growth and further assessed the release of angiogenesis stimulators (VEGF) and angiogenesis inhibitors (endostatin). Italiano confirmed segregation of the stimulators and inhibitors into separate and distinct α-granules. Italiano teaches that the separate packaging of angiogenesis regulators into pharmacologically and morphologically distinct populations of α-granules in megakaryocytes and platelets may provide a mechanism by which platelets can locally stimulate or inhibit angiogenesis.
Lien teaches of two recombinant humanized anti-VEGF antibodies, bevacizumab (Avastin anti-VEGF antibody) and ranibizumab (Lucentis anti-VEGF antibody), for treating tumor cancers, e.g., metastatic colorectal cancer, and having demonstrated therapeutic utility in blocking VEGF-induced angiogenesis (Abstract; 4.2 Clinical Studies with Bevacizumab, page 140).
Therefore, given that Lu teaches production of mature megakaryocytes for subsequent production of a platelet product for transfusion and taking in hand that
Cancer Research teaches that targeting platelet secretory activities may provide a new approach to destabilize tumor vasculature and Italiano teaches that the separate packaging of angiogenesis regulators into pharmacologically and morphologically distinct populations of α-granules in megakaryocytes and platelets may provide a mechanism by which platelets can locally stimulate or inhibit angiogenesis, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to engineer the in vitro produced megakaryocytes to express recombinant humanized anti-VEGF antibodies, e.g., bevacizumab, for the predictable result of producing platelets that block VEGF-induced angiogenesis in tumors, thus meeting the limitations of claim 87-88.
The skilled artisan would have had a reasonable expectation of success in combining the above teachings because each of the teachings are directed at biological therapeutics.
Claim(s) 89-90 are rejected under 35 U.S.C. 103 as being unpatentable over Lu, in view of Figueiredo, as evidenced by Yang, BioLegend and Abcam, as applied to claims 74, 76-82, 84 and 91-92 above, and further in view of Tfayli et al, Medscape.org, 2008, retrieved from the internet; see PTO-892) (“Tfayli”) and Ivashkiv et al., (Trends Immunol. 2012 Dec 4;34(5):216-223; see PTO-892) (“Ivashkiv”).
The teaching of Lu, in view of Figueiredo, as evidenced by Yang, BioLegend and Abcam is set forth above.
Regarding claims 89-90 and the limitations directed to the composition further comprises a BET inhibitor or a c-myc inhibitor (claim 89), and the composition comprises a BET inhibitor, wherein the BET inhibitor is GSK1210151A (I-BET 151) (claim 90), it is noted that Lu does not further comment on the megakaryocyte composition further comprising said inhibitor.
Ivashkiv teaches that iBET and related compounds JQ1 and iBET151 strongly suppress Myc expression and also show great promise for the treatment of Myc-driven cancers such as acute myeloid leukemia (AML) and multiple myeloma (page 220, left col, first paragraph).
Tfayli discusses management of thrombocytopenia in patients with leukemia, e.g. acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and teaches that thrombocytopenia is very common at presentation in patients with acute leukemia (myelogenous and lymphocytic) and since these patients are usually treated with combination chemotherapy to induce remission, thrombocytopenia is essentially universal in these patients and can persist for several weeks until the healthy bone marrow recovers (Introduction, second paragraph). Tfayli teaches that platelet transfusion remains the most common intervention in the management of thrombocytopenia in patients with leukemia (Management, Platelet Transfusion, page 2).
Therefore, given that Ivashkiv teaches I-BET 151 is used for treating cancers such as ALL and AML, and knowing that such patients require platelet transfusions to manage thrombocytopenia that develops in said patients and Lu teaches producing mature megakaryocytes for subsequent production of a platelet product for transfusion, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Lu’s megakaryocytes with the BET inhibitor I-BET 151, as taught by Tfayli.
The person of ordinary skill in the art would have been motivated combine I-BET 151 with Lu’s megakaryocytes for the predictable result of managing thrombocytopenia that develops in patients undergoing I-BET 151 cancer treatment, thus meeting the limitation of claims 89-90.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lu with Ivashkiv and Tfayli because these teachings are directed at hematological treatments.
Claim(s) 93 is rejected under 35 U.S.C. 103 as being unpatentable over Lu, in view of Figueiredo, as evidenced by Yang, BioLegend and Abcam, as applied to claims 74, 76-82, 84 and 91-92 above, and further in view of Gaggar et al., (J Immunol. 2008 Apr 15;180(8):5662–5669; see PTO-892) (“Gaggar”).
The teaching of Lu, in view of Figueiredo, as evidenced by Yang, BioLegend and Abcam is set forth above.
Regarding claim 93, it is noted that Lu teaches the MMP-8 inhibitor GM 6001 and does not further teach the MMP-8 inhibitor is (3R)-(+)-[2– 4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamate] (synonymous with M8I and MMP-8 inhibitor I).
Gaggar discusses the specific multistep proteolytic pathway involved in PGP (proline-glycine-proline) generation from collagen, involving matrix metalloprotease 8 (MMP8), matrix metalloprotease 9 (MMP9) and prolyl endopeptidase, a serine protease for which we identify a novel role in inflammation (Abstract). Table 1 of Gaggar shows that (3R)-(+)-[2– 4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamate] is a MMP-8 inhibitor, having an IC50 = 4 nM.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute (3R)-(+)-[2– 4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamate] for GM 6001 since both are known MMP-8 inhibitors. Therefore, one of ordinary skill in the art would recognize this as simply substituting one MMP-8 inhibitor for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Substitution of one element for another known in the field is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Conclusion
No claim is allowed. No claim is free of prior art.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/ Primary Examiner, Art Unit 1633
