DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Interpretation
Regarding claims 32-35, the recitation “CD8+ T cells armed…a CT-26 tumor antigen” or “CD8+ T cells are armed to… a CT-26 tumor antigen” is interpreted to include any CD8+ T cell as the recited function is inherent to all CD8+ T cells.
Claim Rejections - 35 USC § 112
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.
Claims 32-35 are 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.
The recitation “CD8+ T cells armed…a CT-26 tumor antigen” or “CD8+ T cells are armed to… a CT-26 tumor antigen” renders the claim indefinite” renders claims reading upon said recitation indefinite as this limitation merely states a functional characteristic without providing any indication about how the functional characteristic is provided. It is unclear whether the claim(s) require(s) some structural modification(s) to a CD8+ T cell to provide the functional characteristic or if the functional characteristic is inherent to any/all CD8+ T cell(s). There is nothing inherently wrong with defining some part of an invention in functional terms; however, a functional limitation must be evaluated and considered, just like any other limitation of the claim, for what it fairly conveys to a person of ordinary skill in the pertinent art in the context in which it is used. Functional descriptions of chemical compounds/compositions must be coupled with a known or disclosed correlation between function and structure. For the purposes of applying prior art, the recitation “CD8+ T cells armed…a CT-26 tumor antigen” or “CD8+ T cells are armed to… a CT-26 tumor antigen” is interpreted to include any CD8+ T cell as the recited function is inherent to all CD8+ T cells.
Claim Rejections - 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 20-39 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon (e.g., a natural product) without significantly more. The claim(s) recite(s) a composition comprising “MILs from a cancer patient” that were mobilized out of the bone marrow by at least one E-selectin antagonist. As explained on paragraph [0004] (pages 1-2) of the specification, MILs have been found in patients suffering from hematological malignancies and in metastatic disease arising from solid tumors such as prostate, breast, and lung cancers. A composition comprising MILs from a cancer patient is a nature-based product, so it is compared to its closest naturally occurring counterpart (MILs from a cancer patient in its natural state) to determine if it has markedly different characteristics. Because there is no indication in the record that isolation/mobilization of MILs has resulted in a marked difference in structure, function, or other properties as compared to its counterpart, a composition comprising MILs from a cancer patient is a product of nature exception. This judicial exception is not integrated into a practical application because, as evidenced by Noonan, Kimberly A., et al. "Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma." Science translational medicine 7.288 (2015): 288ra78-288ra78, the mobilization of MILs out of bone marrow of a cancer patient was a well-understood, routine, conventional activity previously engaged in by those in the relevant field. See Figure 1 wherein Noonan describes a standard stem cell mobilization. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because claim(s) do not include additional elements.
Claim Rejections - 35 USC § 102
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.
Claim(s) 20-39 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Noonan, Kimberly A., et al. "Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma." Science translational medicine 7.288 (2015): 288ra78-288ra78 (Noonan).
Noonan teaches that successful adoptive T cell therapy (ACT) requires the ability to activate tumor-specific T cells with the ability to traffic to the tumor site and effectively kill their target as well as persist over time (Abstract). Noonan hypothesized that ACT using marrow-infiltrating lymphocytes (MILs) in multiple myeloma (MM) could impart greater antitumor immunity in that they were obtained from the tumor microenvironment. Noonan describes the results from the first clinical trial using MILs in MM. Twenty-five patients with either newly diagnosed or relapsed disease had their MILs harvested, activated and expanded, and subsequently infused on the third day after myeloablative therapy. Cells were obtained and adequately expanded in all patients with anti-CD3/CD28 beads plus interleukin-2, and a median of 9.5 × 108 MILs were infused. Factors indicative of response to MIL ACT included (i) the presence of measurable myeloma-specific activity of the ex vivo expanded product, (ii) low endogenous bone marrow T cell interferon-g production at baseline, (iii) a CD8+ central memory phenotype at baseline, and (iv) the generation and persistence of myeloma-specific immunity in the bone marrow at 1 year after ACT. Achieving at least a 90% reduction in disease burden significantly increased the progression-free survival (25.1 months versus 11.8 months; P = 0.01). This study demonstrates the feasibility and efficacy of MILs as a form of ACT with applicability across many hematologic malignancies and possibly solid tumors infiltrating the bone marrow.
Noonan hypothesized that because the bone marrow (BM) is the tumor microenvironment for many hematologic malignancies such as MM, marrow-infiltrating lymphocytes (MILs) could be harnessed to generate tumor-specific T cell therapy for these specific cancers (page 1). In contrast to TILs, MILs are present in all patients, can be obtained with a simple bedside procedure, and can be rapidly expanded in all patients. Noonan teaches, in hematologic malignancies, the BM represents not only the site of disease but also a distinctive immunologic microenvironment (pages 1-2). Even in solid tumors, evidence exists that BM-derived T cells can be enriched in memory or effector memory T cells. The immune component within the BM is a reservoir of antigen-experienced T cells for both tumor-specific T cells in host with early-stage breast cancer as well as vaccine-primed T cells. In the BM, memory CD4 cells are in close contact with interleukin-7 (IL-7)–producing stromal cells but not necessarily maintained by either IL-7 or IL-15, and memory CD8 cells are recruited and maintained through the persistence of antigen expression and effective antigen presentation, as well as in response to proliferative signals from IL-7 and IL-15. Hence, the heightened tumor specificity of MILs in this setting is likely due to the presence of tumor as a source of antigen, whereas their persistence is maintained through the immune interactions with stromal elements, cytokines, and APCs capable of effective antigen presentation in this environment.
Noonan teaches that patients received a CD34-selected stem cell product after high-dose melphalan, with a median number of infused CD34+ cells of 7.39 × 106 /kg (03.3 × 106 to 24.2 × 106 /kg) (Fig. 1).
PNG
media_image1.png
350
1008
media_image1.png
Greyscale
Noonan teaches that patients had their MILs collected either at diagnosis, before treatment (n = 4), or before transplant (n = 18) (page 12). To minimize any effects of chemotherapy on the ability to expand the MILs, the chemotherapy was discontinued 3 weeks before the MIL collection. The collection of MILs was an outpatient, bedside procedure in which the patients were given conscious sedation consisting of intravenous fentanyl and midazolam as per standard practice and titrated to patient comfort.
Noonan teaches that the presence of TCM CD8+ phenotype was associated with the highest likelihood of achieving a CR (page 6). This supports studies by others whereby central memory T cells impart better and more durable immunity, as well as have greater persistence in vivo, better antigen recall responses, and improved trafficking to secondary lymphoid organs and, in this case, also to the BM compared to effector memory T cells. Noonan failed to observe any correlation between naïve CD8+ T cells and response and did not examine the presence of the stem cell memory (TSCM) population, both of which have been associated with long-term T cell persistence. However, in light of the data showing minimal numbers of TSCM in the BM (28), Noonan would not expect these cells to correlate with clinical outcomes in our MIL patients. Other features of CD8+ cells correlating with CR included increases in granzyme B, CD107a, and persistent perforin expression.
PNG
media_image2.png
390
978
media_image2.png
Greyscale
Thus, Noonan teaches a composition comprising MILs from a cancer that were mobilized out of the bone marrow. See Fig. 1. Noonan teaches a composition wherein the MILs comprise CD8+ T cells and wherein at least 10% of the CD8+ T cells are naive CD8+ T cells. See Fig. 4. Noonan teaches a composition wherein the MILs comprise CD8+ T cells and wherein at least 40% of the CD8+ T cells are central memory CD8+ T cells. See Fig. 4. Noonan teaches a composition wherein the MILs comprise CD8+ T cells and wherein at least 10% of the CD8+ T cells are naive CD8+ T cells and at least 40% of the CD8+ T cells are central memory CD8+ T cells. See Fig. 4.
Noonan differs from the instantly claimed invention in that Noonan does not explicitly teach a composition wherein the MILs were mobilized out of the bone marrow by at least one E-selectin antagonist selected from
PNG
media_image3.png
192
640
media_image3.png
Greyscale
and
PNG
media_image4.png
200
678
media_image4.png
Greyscale
; however, because there is no indication in the record that isolation/mobilization of MILs has resulted in a marked difference in structure, function, or other properties the MILs composition(s) of Noonan is embraced by the instantly claimed composition. Thus, claims 20-39 are anticipated.
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) 20-37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Noonan, Kimberly A., et al. "Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma." Science translational medicine 7.288 (2015): 288ra78-288ra78 (Noonan) and Magnani WO 2014/089269 A1 (Magnani) in combination.
Claims 20-37 are drawn to a composition comprising MILs from a cancer patient that were mobilized out of the bone marrow by at least one E-selectin antagonist chosen from
PNG
media_image3.png
192
640
media_image3.png
Greyscale
and
PNG
media_image4.png
200
678
media_image4.png
Greyscale
.
Noonan teaches that successful adoptive T cell therapy (ACT) requires the ability to activate tumor-specific T cells with the ability to traffic to the tumor site and effectively kill their target as well as persist over time (Abstract). Noonan hypothesized that ACT using marrow-infiltrating lymphocytes (MILs) in multiple myeloma (MM) could impart greater antitumor immunity in that they were obtained from the tumor microenvironment. Noonan describes the results from the first clinical trial using MILs in MM. Twenty-five patients with either newly diagnosed or relapsed disease had their MILs harvested, activated and expanded, and subsequently infused on the third day after myeloablative therapy. Cells were obtained and adequately expanded in all patients with anti-CD3/CD28 beads plus interleukin-2, and a median of 9.5 × 108 MILs were infused. Factors indicative of response to MIL ACT included (i) the presence of measurable myeloma-specific activity of the ex vivo expanded product, (ii) low endogenous bone marrow T cell interferon-g production at baseline, (iii) a CD8+ central memory phenotype at baseline, and (iv) the generation and persistence of myeloma-specific immunity in the bone marrow at 1 year after ACT. Achieving at least a 90% reduction in disease burden significantly increased the progression-free survival (25.1 months versus 11.8 months; P = 0.01). This study demonstrates the feasibility and efficacy of MILs as a form of ACT with applicability across many hematologic malignancies and possibly solid tumors infiltrating the bone marrow.
Noonan hypothesized that because the bone marrow (BM) is the tumor microenvironment for many hematologic malignancies such as MM, marrow-infiltrating lymphocytes (MILs) could be harnessed to generate tumor-specific T cell therapy for these specific cancers (page 1). In contrast to TILs, MILs are present in all patients, can be obtained with a simple bedside procedure, and can be rapidly expanded in all patients. Noonan teaches, in hematologic malignancies, the BM represents not only the site of disease but also a distinctive immunologic microenvironment (pages 1-2). Even in solid tumors, evidence exists that BM-derived T cells can be enriched in memory or effector memory T cells. The immune component within the BM is a reservoir of antigen-experienced T cells for both tumor-specific T cells in host with early-stage breast cancer as well as vaccine-primed T cells. In the BM, memory CD4 cells are in close contact with interleukin-7 (IL-7)–producing stromal cells but not necessarily maintained by either IL-7 or IL-15, and memory CD8 cells are recruited and maintained through the persistence of antigen expression and effective antigen presentation, as well as in response to proliferative signals from IL-7 and IL-15. Hence, the heightened tumor specificity of MILs in this setting is likely due to the presence of tumor as a source of antigen, whereas their persistence is maintained through the immune interactions with stromal elements, cytokines, and APCs capable of effective antigen presentation in this environment.
Noonan teaches that patients received a CD34-selected stem cell product after high-dose melphalan, with a median number of infused CD34+ cells of 7.39 × 106 /kg (03.3 × 106 to 24.2 × 106 /kg) (Fig. 1).
PNG
media_image1.png
350
1008
media_image1.png
Greyscale
Noonan teaches that patients had their MILs collected either at diagnosis, before treatment (n = 4), or before transplant (n = 18) (page 12). To minimize any effects of chemotherapy on the ability to expand the MILs, the chemotherapy was discontinued 3 weeks before the MIL collection. The collection of MILs was an outpatient, bedside procedure in which the patients were given conscious sedation consisting of intravenous fentanyl and midazolam as per standard practice and titrated to patient comfort.
Noonan teaches that the presence of TCM CD8+ phenotype was associated with the highest likelihood of achieving a CR (page 6). This supports studies by others whereby central memory T cells impart better and more durable immunity, as well as have greater persistence in vivo, better antigen recall responses, and improved trafficking to secondary lymphoid organs and, in this case, also to the BM compared to effector memory T cells. Noonan failed to observe any correlation between naïve CD8+ T cells and response and did not examine the presence of the stem cell memory (TSCM) population, both of which have been associated with long-term T cell persistence. However, in light of the data showing minimal numbers of TSCM in the BM (28), Noonan would not expect these cells to correlate with clinical outcomes in our MIL patients. Other features of CD8+ cells correlating with CR included increases in granzyme B, CD107a, and persistent perforin expression.
PNG
media_image2.png
390
978
media_image2.png
Greyscale
Thus, Noonan teaches a composition comprising MILs from a cancer that were mobilized out of the bone marrow. See Fig. 1. Noonan teaches a composition wherein the MILs comprise CD8+ T cells and wherein at least 10% of the CD8+ T cells are naive CD8+ T cells. See Fig. 4. Noonan teaches a composition wherein the MILs comprise CD8+ T cells and wherein at least 40% of the CD8+ T cells are central memory CD8+ T cells. See Fig. 4. Noonan teaches a composition wherein the MILs comprise CD8+ T cells and wherein at least 10% of the CD8+ T cells are naive CD8+ T cells and at least 40% of the CD8+ T cells are central memory CD8+ T cells. See Fig. 4.
Noonan differs from the instantly claimed invention in that Noonan does not explicitly teach a composition wherein the MILs were mobilized out of the bone marrow by at least one E-selectin antagonist selected from
PNG
media_image3.png
192
640
media_image3.png
Greyscale
and
PNG
media_image4.png
200
678
media_image4.png
Greyscale
; however, this deficiency would have been obvious in view of the teachings of Magnani.
In the instant case, the references may be combined to show obviousness because Noonan and Magnani are each drawn to a method of mobilizing cells from bone marrow. They are from the same field of endeavor, and/or are reasonably pertinent to a composition comprising MILs from a cancer patient that were mobilized out of the bone marrow by at least one E-selectin antagonist chosen from
PNG
media_image3.png
192
640
media_image3.png
Greyscale
and
PNG
media_image4.png
200
678
media_image4.png
Greyscale
.
Magnani teaches agents that are E-selectin antagonists, compositions comprising the agents, and methods for using the agents (page 2). These agents are useful for mobilizing cells from the bone marrow, including hematopoietic cells, such as hematopoietic stem cells and progenitor cells and white blood cells, such as granulocytes (including neutrophils). A method is provided for mobilizing cells from the bone marrow in a subject comprising administering to the subject a compound (which is a giycomimetic compound that is an E-selectin antagonist) having the following formula (I):
PNG
media_image5.png
318
572
media_image5.png
Greyscale
or a pharmaceutically acceptable salt, isomer, tautomer, hydrate or solvate thereof. In particular embodiments, the compound of formula (I) is compound 25 (page 23).
PNG
media_image6.png
248
868
media_image6.png
Greyscale
Magnani teaches that Compound 25 with an average IC50 of 2.4 µM showed competitive inhibition of E-selectin at concentrations substantially lower than the reference compound, Compound 77, which had an average IC50 of 4.33 µM (page 60). Compound 25 selectively and potently inhibits the binding of E-selectin.
Magnani teaches that the E-selectin antagonist agents described therein, including glycomimetics, antibodies or antigen-binding fragments thereof, polypeptides, peptides and aptamers may be useful in methods for mobilizing cells from the bone marrow to the peripheral vasculature and tissues (page 40). As discussed therein, in certain embodiments, the E-selectin antagonist agents are useful for mobilizing hematopoietic cells, including hematopoietic stem cells and hematopoietic progenitor cells. As described therein, E-selectin compounds act as mobilizing agents of normal blood cell types. Accordingly, in other embodiments, the agents are used in methods for mobilizing mature white blood cells (which may also be called leukocytes therein), such as granulocytes (e.g., neutrophils, eosinophils, basophils), lymphocytes, and monocytes from the bone marrow or other immune cell compartments such as the spleen and liver. In other embodiments, the methods described therein are useful for mobilizing hematopoietic leukocytes (white blood cells) in a subject, which methods may be used in treating diseases, disorders, and conditions for which an increase in white blood cells, such as neutrophils, eosinophils, lymphocytes, monocytes, basophils, will provide clinical benefit (page 42).
In determining the differences between the prior art and the claims, the question under 35 U.S.C. 103 is not whether the differences themselves would have been obvious, but whether the claimed invention as a whole would have been obvious. Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 218 USPQ 871 (Fed. Cir. 1983); Schenck v. Nortron Corp., 713 F.2d 782, 218 USPQ 698 (Fed. Cir. 1983).
It would have been obvious to one of ordinary skill in the art at the time of filing to substitute the standard stem cell mobilization agent (e.g., cyclophosphamide and G-CSF) employed in the method of Noonan with E-selectin antagonist compound 25 of Magnani. As set forth above, Magnani teaches that the E-selectin antagonist agents described therein may be useful in methods for mobilizing cells from the bone marrow to the peripheral vasculature and tissues. The simple substitution of one known element (e.g., mobilization agent(s)) for another to obtain predictable results is prima facie obvious. The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art. One would have had a reasonable expectation of success as Magnani 1) teaches methods for mobilizing mature white blood cells (which may also be called leukocytes therein) such as lymphocytes and 2) teaches that Compound 25 showed competitive inhibition of E-selectin at concentrations substantially lower than the reference compound.
All of the instant limitations are taught by the combination of Noonan and Magnani. A person of ordinary skill in the art would have had a reason to combine the teachings of Noonan and Magnani. A person of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Noonan and Magnani. Thus, claims 20-37 would have been obvious based on the preponderance of the evidence.
Conclusion
Claims 20-39 are pending. Claims 20-39 are rejected. No claims are allowed.
Contacts
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PATRICK T LEWIS whose telephone number is (571)272-0655. The examiner can normally be reached Monday to Friday, 10 AM to 4 PM EST (Maxi Flex).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Deirdre Claytor can be reached at (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/PATRICK T LEWIS/Primary Examiner, Art Unit 1691
/PL/