leNotice 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 .
Double Patenting
Claims 4, 5, 7, 8, 13, 19, 25, 28-31, 35, and 37 of this application is patentably indistinct from claims 1, 2, 4, 5, 10, 11, 14, 16, 18, 19, 21, 24, 30, 33, 37, 43, 47, 49, 50, and 52 of Application No. 18/556,827. 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 7 and 37 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 7 and 37 recite the following broad recitations:
Claim 7: “further comprising administering a corticosteroid”
Claim 37: “wherein the subject is taken off the ventilator after treatment”
The claims also recite “preferably” which is the narrower statement of the range/limitation respective to the following limitations:
Claim 7: “preferably wherein the corticosteroid is dexamethasone”
Claim 37: “preferably wherein the subject is taken off a ventilator within 60 days of treatment”
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 § 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.
Claims 4, 5, 7, 8, 13, 16, 17, 18, 19, 25, 28, 29, 30, 31, 35, 37, 40, 42, and 43 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 Schinazi et al. (CA 3139977 A1), Gondim et al. (Influence of buffer solution the adsorption of human serum proteins onto layered double hydroxide), and Mirabel et al. (Stability enhancement of clinical grade multipotent mesenchymal stromal cell-based products, 2018) as evidenced by Diamond et al, (Acute Respiratory Distress Syndrome, 2024), Leng et al. (Transplantation of ACE2-Mesenchymal Stem Cells improves the Outcome of Patients with COVID-19 Pneumonia, 2020), and Welly.com
Regarding claims 4 and 5: Atluri teaches 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) Atluri further teaches 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)
Alturi fails to teach use 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.
Regarding claim 7: Atluri teaches in one of the studies discussed that patients requiring mechanical ventilation had severe ARDS. (Pg E72, Introduction) Atluri further teaches 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 8: Atluri teaches a trial in which a 65 year old woman required mechanical ventilation who was treated with stem cell therapy. (Pg E75, 5.0)
Regarding claim 13: Atluri teaches a trial which utilized expanded umbilical cord mesenchymal stem cells to treat acute respiratory distress syndrome caused by COVID-19. (Pg E71, Introduction)
Regarding claims 16-18: Atluri references a study by Leng, et al. in which 7 participants with COVID-19 presented with common to severe symptoms as defined in the table below:
PNG
media_image1.png
196
770
media_image1.png
Greyscale
By the end of the 14 day observation window and after treatment with MSCs, the patient outcomes were as follows:
PNG
media_image2.png
364
778
media_image2.png
Greyscale
As can be seen, out of the three control patients one patient did not survive, resulting in a mortality rate in the control group of ~33%. Out of seven experimental patients, all seven patients survived, resulting in a mortality rate in the test group of 0%, showing a reduction in mortality rate by ~33%. This satisfies the following claims:
Claim 16: the treated subject’s risk of mortality is reduced after treatment
Claim 17: The treated subject’s risk of mortality is reduced between 30% and 60%.
Claim 18: The treated subject has improved 60 day survival.
Regarding claim 19: 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 25: Atluri teaches use of allogenic umbilical cord stem cells. (Pg E75, 5.0)
Regarding claims 28 and 29: Atluri references a study by Leng et al. who states a dose of 1x10^6 cells per kg of body weight. (Pg 218, Materials and Methods) The study takes place in China, specifically Shanghai University. Per Welly.com, the average body weight of the male population of China is 69.6 kg and the average body weight of the female population of China is 59 kg. The dose range required by claims 28 and 29 is between 1x10^7 and 2x10^8 cells per dose, and the dose referenced by Leng is 1x10^6 cells per kg of body weight. When the dose provided by Leng is calculated based on the respective average weights of the population of China, the expected average dose is 5.9x10^7 cells per dose for women and ~6.9x10^7 cells per dose for men. As such, the dose referenced by Leng reads on both the requirement of claim 28 (between 1x10^7 and 2x10^8 cells per dose) and claim 29 (about 1x10^8 cells per dose).
Regarding claims 30 and 31: 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. of body weight. (Pg E76, 5.0) Although Atluri referenced a study administering three doses, per MPEP 2144.05.1, a claimed range (in this case, 2 doses) may lie within a broader range (3 doses) disclosed by the prior art.
Regarding claim 35: 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:
PNG
media_image3.png
164
366
media_image3.png
Greyscale
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.
Regarding claim 37: 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 claim 40: 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)
Regarding claim 42: Atluri discloses that patients enrolled in a stem cell therapy clinical trial to treat symptoms from mild to severe COVID-19, by day 14 all patients in the treated group had biomarkers, including CRP, return to normal levels. (Pg E75, 5.0)
Regarding claim 43: Atluri teaches in one of the studies discussed that patients requiring mechanical ventilation had severe ARDS. (Pg E72, Introduction) It would be known to a person skilled in the art that ARDS is diagnosed and defined by the Berlin criteria, as evidenced by Diamond et al. who states “according to the Berlin definition, ARDS is defined by acute onset, bilateral lung infiltrates…and a PaO2/FiO2 ratio of less than 300 mm Hg.” (Pg 1, Introduction) As such, it would be inherent that a patient diagnosed with ARDS would have met the Berlin criteria. In addition to this, as evidenced by Leng, patients enrolled in the study having severe or greater COVID-19 present with respiratory distress, FiO2 or under 300 mmHg, and even patients with common COVID-19 require pneumonia performance on x-ray. (Pg 3, Table 1) As such, it is further inherent that patients enrolled in the trial by Leng had ARDS as defined in the Berlin criteria, and showed symptomatic improvement regarding respiratory function as a result of the study.
Claim 14 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), Gondim et al. (Influence of buffer solution the adsorption of human serum proteins onto layered double hydroxide), Mirabel et al. (Stability enhancement of clinical grade multipotent mesenchymal stromal cell-based products, 2018), and Iglesias et al. (Mesenchymal Stem Cells for the Compassionate Treatment of Severe Acute Respiratory Distress Syndrome Due to COVID 19, 2021)
The teachings of Atluri, Schinazi, Gondim, and Mirabel are discussed above. All fail to teach that the patients treated with stem cells had some form of thrombosis.
Regarding claim 14: Iglesias teaches the administration of allogenic human umbilical cord stem cells in patients with bilateral pneumonia caused by COVID-19. (Pg 360, Abstract) Of the patients, one had arterial thrombosis in the left lower limb fifteen days post-MSC infusion. (Pg 366, Results) The study resulted in the infusion of MSCs causing reduction in inflammation in the lungs and improved respiratory function, with three patients being extubated on the ninth day post infusion. (Pg 360, Abstract)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the stem cell treatment method taught by Atluri on patients with thrombosis as taught by Iglesias. A person skilled in the art would have had motivation and a reasonable expectation of success due to the teachings of Iglesias, who demonstrate that use of MSCs as a treatment for COVID-19 improved respiratory function and reduced inflammation in the lungs.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNA M THUESON whose telephone number is (571) 272-3680. The examiner can normally be reached M-F 7:30-5 EST. 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, Tracy Vivlemore, can be reached on (571) 272-2914. 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.
/HANNA MARIE THUESON/ Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
Prosecution Insights