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 Objections
Claims 18 and 49 use improper Markush language, specifically “selected from the list comprising” (claim 18) and “selected from the group comprising” (claim 49). This language should be amended to “selected from the list/group consisting” to reflect the requirement of only one or more of the listed components in order to satisfy the claim.
Double Patenting
Claims 1, 2, 4, 5, 10, 11, 14, 16, 18, 19, 21, 24, 30, 33, 37, 43, 47, 49, 50, and 52 of this application are patentably indistinct from claims 4, 5, 7, 8, 13, 19, 25, 28-31, 35, and 37 of Application No. 18/556,845. Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
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 5, 18, 19, and 21 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 5, 18, 19, and 21 recite the following broad recitations:
Claim 5: “wherein the CCR-2binding chemokine(s) is CCL2, CCL3, or CCL7…wherein CXCR3-binding chemokine is CXCL10 or CXCL9”
Claim 18: “selected from the list comprising: (i) a CXCR3 binding chemokine… (ii) a CCR2-binding chemokine…”
Claim 19: “a CXCR3-binding chemokine… - CCR2-binding chemokine”
Claim 21: “wherein treatment improves respiratory function in the subject”
The claims also recite “preferably” which is the narrower statement of the range/limitation respective to the following limitations:
Claim 5: “preferably CCL2, wherein CXCR3-binding chemokine is CXCL10 or CXCL9, preferably CXCL10”
Claim 18: “preferably CXCL10, and/or CXCL9… preferably CCL2, CCL3, and/or CCL7… preferably CXCL10, and/or CXCL9…preferably CCL2, CCL3, and/or CCL7”
Claim 19: “preferably CXCL10, and/or CXCL9…preferably CCL2, CCL3, and/or CCL7”
Claim 21: “preferably wherein respiratory function as defined by Berlin criteria is improved at day 14 and/or day 21”
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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) 1, 2, 4, 5, 10, 11, 14, 16, 18-19, 21, 24, 33, 43, 49, 50, and 52 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Atluri et al. (Expanded Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) as a Therapeutic Strategy In Managing Critically Ill COVID-19 Patients: The Case for Compassionate Use, 2020) as evidenced by Wyczalkowska-Tomasik et al. (Inflammatory Markers Change with Age, but do not Fall Beyond Reported Normal Ranges, 2015) and Leng et al. (Transplantation of ACE2-Mesenchymal Stem Cells improves the Outcome of Patients with COVID-19 Pneumonia, 2020)
Regarding claim 1: Atluri discloses a trial which utilized expanded umbilical cord mesenchymal stem cells to treat acute respiratory distress syndrome caused by COVID-19. (Pg E71, Introduction) In one trial, a 65 year old woman who required mechanical ventilation was treated with 3 doses of 50 million allogenic umbilical cord stem cells in conjunction with conventional therapy. (Pg E75, 5.0) Regarding the claimed dose of greater than 4 million MLPSCs per kg of body weight, Atluri discusses a different planned study which uses 5.0x10^6 cells/kg. (Pg E76, 5.0)
Regarding claim 2: Atluri states that during COVID-19 infection, the immune system releases a large number of inflammatory biomarkers which result in a severe cytokine storm, possibly inducing organ damage. (Pg E71, Introduction) As is stated in claim 2, this cytokine storm indicates increased neutrophil and macrophage influx and T cell activation.
Regarding claim 4: Following the discussion of claim 1, the 65 year old patient referenced in the study was on a ventilator.
Regarding claim 5: Atluri discloses that when the immune system is overactivated, it releases a cytokine storm including IL-2. (Pg E73, 2.0) As claim 5 states, this indicates T cell activation and proliferation, as well as apoptotic death.
Regarding claims 10 and 11: Atluri discloses that during COVID-19 infection, a cytokine storm causes increased levels of biomarkers including IL-2 and IL-6. (Pg E73, 2.0) Atluri fails to disclose explicitly that the increased levels of biomarkers are twofold or greater than that of a subject who is less than 65 years old. However, Wyczalkowska-Tomaski discloses that serum levels of IL-6 , CRP, and TNF-R1 were greater in participants over 65 years of age, even in healthy individuals. (Pg 249, Introduction) Furthermore, Wyczalkowska-Tomaski discloses that when measured, serum levels of IL-6 is greater than two fold times higher in a patient over 50 years of age than a patient in their 20’s and CRP levels are doubled in patients 50-60 years old compared to a patient in their 20’s, as shown in the table below:
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As the above numbers were derived from healthy individuals, it is inherent that a subject who is greater than 65 years of age will have increased inflammatory biomarkers when compared to a subject who is less than 65 years old, regardless if the subjects are healthy or infected with COVID-19.
Regarding claim 14: Atluri discloses that the subject, after being treated with 3 doses of 50 million allogenic umbilical cord stem cells, had CRP levels that had returned to normal. (Pg E76, 5.0)
Regarding claim 16: Atluri states that, after treatment with allogenic umbilical cord stem cells, the 65 year old woman no longer required mechanical ventilation. (pg E75, 5.0)
Regarding claims 18 and 19: Atluri discloses that seven patients enrolled in a study where they received stem cell therapy had biomarkers for inflammation monitored for 14 days during the trial, and that at the end of 14 days said biomarkers, including CRP, had returned to normalized levels. As evidenced by Leng (the study referenced by Atluri), all patients had shortness of breath and low oxygen saturation prior to treatment (pg 220, the primary safety outcome) and Leng further states that all infected ICU patients suffer from acute respiratory distress syndrome. (Pg 226, Discussion) Furthermore, the ages of the patients enrolled in the study ranged from 45-75 years old. (Pg 219, Table 2)
Regarding claim 21: Atluri discloses that patients enrolled in a stem cell therapy clinical trial to treat symptoms from mild to severe COVID-19, all patients in the treated group had biomarkers, including CRP, return to normal levels. (Pg E75, 5.0)
Regarding claim 24: Atluri discloses that the 65 year old patient received 3 doses of 50 million allogenic umbilical cord stem cells with each dose being three days apart. Furthermore, Atluri discloses another study in which the patients will receive 5.0x10^6 cells/kg. of body weight. (Pg E76, 5.0)
Regarding claim 33: Atluri discloses in one of the studies discussed that patients requiring mechanical ventilation had severe ARDS. (Pg E72, Introduction) Atluri further discloses that in a different study, a 65 year old patient had severe pneumonia and respiratory failure prior to receiving stem cell treatment and recovering. (Pg E75, 5.0)
Regarding claim 43: Atluri discloses use of allogenic umbilical cord stem cells. (Pg E75, 5.0)
Regarding claims 49 and 52: Atluri discloses a study in which 7 patients were followed for 14 days and monitored for inflammatory biomarkers such as CRP, which by the end of the study had returned to normalized baseline levels. As evidenced by Leng in Table 4 pictured below, CRP levels of the critical patient were monitored at the beginning, during, and at the end point of the study as shown below:
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Alturi further references multiple studies which use doses ranging from 0.5x10^6 to 5.0x10^6 cells/kg (pg E76, 5.0), which encompasses the claimed range of 4 million MLPSCs per kg of body weight. As Leng evidences that the inflammatory biomarker CRP decreased, indicating that the inflammation status was quickly being alleviated (Pg 220, The efficacy outcome), further doses were not needed, rendering claim 52 obsolete.
Regarding claim 50: Atluri discusses one study in which CRP was normalized by day 14. (Pg E76, 5.0)
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.
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Atluri et al. (Expanded Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) as a Therapeutic Strategy In Managing Critically Ill COVID-19 Patients: The Case for Compassionate Use, 2020) in view of Schinazi et al. (CA 3139977 A1) as evidenced by Leng et al. (Transplantation of ACE2-Mesenchymal Stem Cells improves the Outcome of Patients with COVID-19 Pneumonia, 2020) and Chan et al. (Dexmethasone treatment for the acute respiratory distress syndrome, 2020)
The teachings of Atluri are discussed above. Atluri fails to teach administration of a corticosteroid or the specific dose of 4 million MSCs per kg of body weight.
Regarding claim 30: Atluri fails to teach use of cotreatment in the form of a corticosteroid. Schinazi teaches compounds and methods for treating a coronavirus in human and animal hosts. (Pg 1, Abstract) Specifically, Schinazi states that corticosteroids may be used in combination therapy for the treatment of coronaviruses. (Pg 75, Additional Compounds that can be Used) In addition to this, Chan et al. teaches that studies looking at the success rate of using dexamethasone for the treatment of acute respiratory distress syndrome may decrease the duration a patient may require mechanical ventilation and mortality rates. (Pg 1, Introduction)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Schinazi with the teachings of Atluri of use of a corticosteroid along with administration of MSCs to treat ARDS. A person of ordinary skill in the art would have been motivated and had a reasonable expectation of success based on Schinazi, who states use of combination therapy involving corticosteroids as evidenced by Chan, who teaches that specifically Dexamethasone improves mortality rates and lessens mechanical ventilation time.
Claims 37 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Atluri et al. (Expanded Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) as a Therapeutic Strategy In Managing Critically Ill COVID-19 Patients: The Case for Compassionate Use, 2020) in view of Mirabel et al. (Stability enhancement of clinical grade multipotent mesenchymal stromal cell-based products) and Gondim et al. (Influence of buffer solution the adsorption of human serum proteins onto layered double hydroxide)
The teachings of Atluri are discussed above. Atluri fails to teach use of a medium composition comprising Plasma-Lyte A, DMSO, and human serum albumin (hereafter “HSA”) and use of cells that have been cryopreserved.
Regarding claim 37: Atluri fails to teach that the stem cells of the composition were cryopreserved. Mirabel teaches that cryopreservation in a way that results in high viability contributes as a tool to overcome challenges in manufacturing, formulation, and handling (Pg 2, Background) and that cryopreservation allows for the banking of cells, thus postponing their expiration. (Pg 1, Background)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the use of cryopreservation taught by Mirabel with the composition taught by Atluri. One skilled in the art would have had motivation and a reasonable expectation of success based on the teachings of Mirabel, who state that cryopreservation of cells allows for the banking of cells, thus postponing their expiration.
Regarding claim 47: Atluri teaches doses of the composition ranging from 0.5x10^6 to 5.0x10^6 cells/kg (pg E76, 5.0), reading on the composition comprising greater than 6.68x10^6 viable cells. Atluri fails to teach use of the composition comprising plasma-lyte at 70%, DMSO at 10%, and HSA solution at 25%, wherein the solution comprises 5% HSA and 15% buffer.
Mirabel teaches the effect of different formulations on the stability and potency of MSCs. (Pg 1, Results) Specifically, Mirabel teaches use of Prochymal, which is a type of cryopreserved cell-based medicine which utilizes human MSCs suspended in 10% DMSO and 5% HSA in Plasma-Lyte, which is produced from a single donor and expanded into large batches. (Pg 8, Discussion) Use of Prochymal allows the cells to be cryopreserved, allowing for off-the-shelf banked cells to be made immediately available for patients who need treatment. (Pg 8, Discussion) Both Mirabel and Atluri fail to teach use of HSA being in a buffered solution.
Gondim teaches how different buffers impact the adsorption rates of HAS. (Pg 1, Abstract) It was found that adsorption capacity is directly related to the pH of a medium (Pg 1, Introduction) and that of all the buffers tried, use of acetate resulted in the highest update of HSA, as shown in the table below:
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While Gondim fails to teach exactly the use of 15% buffer and 5% HSA, the exact percentages used would easily be determined via routine optimization throughout the experimental process. (reference MPEP 2144.05.II)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Mirabel and Gondim with the stem cell composition taught by Atluri to create a composition that had at one point been cryopreserved and comprised human stem cells suspended in 10% DMSO and 5% HSA in Plasma-Lyte. A person skilled in the art would have had motivation and a reasonable expectation of success based on the teachings of Mirabel, who teach that use of Prochymal allows for cryopreservation of the cells, which makes their therapeutic potential immediately available when patients are in need and Gondim, who teaches that use of a pH buffer increased adsorption of HSA.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNA MARIE THUESON whose telephone number is (571)272-3680. The examiner can normally be reached Monday-Friday 8:30-5.
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/HANNA MARIE THUESON/Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638