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 .
Claims 1-23, 25-49 have been canceled. Claim 24 remains pending.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim interpretation
Support for --- such that symptoms of CP are decreased in the human--- is found in the Results on pg 24-29.
Election/Restrictions
Applicants elected Group I, claims 24-37, without traverse in the reply filed on 06/04/2021.
Claim 24 remains pending and under consideration.
35 USC § 112
Written Description
The rejection regarding injecting a single dose of 2x107 allogeneic human cord blood stem cells/kg intrathecally to a human with CP who is 10 years old or younger such that symptoms of CP are decreased in claim 24 has been withdrawn in view of the amendment which deletes the concept of intrathecal administration.
Enablement
The rejection regarding injecting a single dose of 2x107 allogeneic human cord blood stem cells/kg intrathecally to a human with CP who is 10 years old or younger such that symptoms of CP are decreased in claim 24 has been withdrawn in view of the amendment which deletes the concept of intrathecal administration.
35 USC § 103 - Claim Rejections
A) Claim 24 remains rejected under 35 U.S.C. 103 as being unpatentable over Feng (Stem Cells, 2015, Article ID 325652, pg 1-7) as supported by “Average height and Weight Babies to Teenagers” (2023) and Ramanov (EP 2298328).
Feng administered allogeneic umbilical CBMCs to patients with CP intravenously (title, abstract, pg 2, col. 1, 2.2 “Cell infusion and patient monitoring”; pg 2, last partial paragraph for 1-29 years). Intravenous injection is “systemically” as required in claims 24 and 25. The children were 1 year old (pg 2, last partial paragraph) which is less than 10 years old as required in claim 24.
Feng administered 2x107 CBMCs/kg over 4-8 injections as follows: Feng administered 2-3x107 cells/dose 4-8 times (pg 2, section 2.2) to patients with an average mean age of 5.85 (pg 3, Table 1). The average weight of a 5 year old female is 17.92 and a 5 year old boy is 18.37 kg; the average weight of a 6 year old female is 19.96 and a 5 year old boy is 20.64 kg. 2-3x107 cells/injection x 4-8 injections is 8x107 – 1.6x108 cells (see “Average height and Weight Babies to Teenagers”). For a child that is 17.92 kg, that is 8.93x107 cell/kg which is at least 2x107 cells/kg as required in claim 24. The total number of cells per kilogram described by Feng was over 2x107 allogeneic CBMCs/kg.
Feng did not administer one dose of 2x107 cells/kg as required in claim 24. However, it would have been obvious to do administer the cells all at once to decrease visits to the clinic. Those of ordinary skill in the art at the time of filing would have been motivated to reduce the number of doses to one dose to improve efficiency. Modifying the dosage was well within the purview of the ordinary practitioner at the time of filing as evidenced by Feng. Those of ordinary skill in the art at the time of filing would have been motivated to administer one dose of 2x107 cells/kg to patients as required in claim 24 as a matter of optimization.
Ramanov taught “unexpectedly to the authors of this invention, they have discovered that the umbilical cord blood nucleated cells are highly effective if applied as a single injection of umbilical cord blood cells to patients” (pg 8, para 59). Therefore, those of skill would have had a reasonable expectation of successful treatment using a single dose as claimed.
The method of Feng as written MUST inherently result in decreased symptoms of CP including improved motor function for “at least 12 month after administering the single dose” as required in claim 24 because the allogeneic CBMCs, route of administration, and total number of allogeneic CMBCs used by Feng are EXACTLY the same type of cell, route of administration, and number of cells as those used by applicants. Feng taught “Several preclinic and clinic trials now show that allogeneic UCBSCs have therapeutic effects for CP” (pg 1, 2nd para). Therefore, the protocol of Feng without modification MUST inherently result in the therapeutic effect claimed.
Modifying the protocol of Feng to one dose also MUST inherently result in the therapeutic effect claimed because the type of cell, route of administration, dosage schedule, and number of cells are EXACTLY those used by applicants and claimed.
Response to arguments
Applicants argue the lack of teaching by Feng of a single dose of 2-3x107 cells “is not a minor variation, but a fundamentally different regimen requiring repeated administrations over time”. Applicants’ argument is not persuasive. A single dose was well-known as evidenced by Romanov (“unexpectedly to the authors of this invention, they have discovered that the umbilical cord blood nucleated cells are highly effective if applied as a single injection of umbilical cord blood cells to patients” - pg 8, para 59). The fact that Feng did not use a single dose of the amount of cells claimed is not a major variation; it’s an obvious variation.
Applicants argue the examiner’s motivational statement to “administer the cells all at once to decrease visits” lacks evidence. Applicants’ argument is not persuasive. Evidence is not needed for the well-known desire to save time. Especially when it was well-known that a single dose of umbilical cord nucleated cells were “highly effective” as described by Romanov.
Applicants conclude the examiner has used impermissible hindsight. Applicants’ argument is not persuasive for reasons in the two paragraphs above. It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicants argue reliance upon Romanov is improper because Romanov used multiple doses and a single dose of umbilical cord nucleated cells for treatment of CP in children under 10 using different dosing amounts which appears as though applicants are attempting to argue Romanov taught away from using one dose (pg 6). Applicants end the paragraph saying Romanov undermines “expectation of success” (which conflates arguments). Applicants’ arguments are not persuasive. Romanov cannot undermine any expectation of success. Romanov is proof that those of skill knew a single dose would be successful in treating CP in children under 10. In fact, Romanov is proof that those of skill knew many dosage amounts and frequencies were successful in treating CP in children under 10.
Applicants argue the examiner’s reliance upon inherency in Feng is misplaced (pg 7). Applicants’ argument is not persuasive. The allogeneic CBMCs, route of administration, and total number of allogeneic CMBCs used by Feng are EXACTLY the same type of cell, route of administration, and number of cells as those used by applicants. Feng taught “Several preclinic and clinic trials now show that allogeneic UCBSCs have therapeutic effects for CP” (pg 1, 2nd para). Therefore, the protocol of Feng without modification to a single dose MUST inherently result in the therapeutic effect claimed. While Feng did not test motor function or teach whether the treatment lasted at least 12 months, the combination of Feng and Romanov MUST inherently result in the therapeutic effect claimed because allogeneic CBMCs, route of administration, total number of allogeneic CMBCs, and dosage frequency taught by the combination of Feng and Romanov are EXACTLY the same as those claimed.
Applicants argue the Examiner improperly assumes treatment outcomes are a function of cell number and dosing. Applicants’ argument is not persuasive. The Examiner is simply setting forth what was well-known and described by Feng and Romanov, all of where successfully treated CP.
Applicants argue unexpected results were obtained (pg 7-8). Applicants argue Feng used 4-8 injections and Romanov taught multiple infusions. Applicants’ arguments are not persuasive. Romanov taught a single dose had a therapeutic effect and is not limited to multiple doses. Furthermore, an unexpected results argument must begin with what was expected. Feng administered the same number of cells intravenously to children under 10 and successfully ameliorated symptoms of CP in four doses instead of one; the teachings of Feng are exactly the same as those in claim 24 except for using a single dose. Applicants’ arguments do not teach what was expected from Feng regarding symptoms of CP were motor function after 12 months. If applicants have proof that the method of Feng failed to improve motor function, please provide such evidence. If applicants have proof that the method of Feng failed to improve symptoms of CP for 12 months, please provide such evidence. Claim 24 has a phenotype that wasn’t tested by Feng, but applicants have not provided evidence that the phenotype did not occur in Feng.
Applicants argue the examiner’s assertion of a single dose being a matter of optimization is unsupported. Applicants’ argument is not persuasive. Feng and Romanov taught numerous combinations of amounts and frequencies of dosages that successfully treated symptoms of CP. Romanov specifically taught a single dose was a valid option for obtaining a therapeutic effect. A single dose was a specific, valid, and obvious choice for optimization based on the art at the time of filing, science, and logic.
B) Claim 24 remains rejected under 35 U.S.C. 103 as being unpatentable over Lee (J. Transl. Med., 2012, Vol. 10, No. 58, pg 1-11) in view of Feng (Stem Cells, 2015, Article ID 325652, pg 1-7) and Ramanov (EP 2298328).
Lee administered autologous umbilical cord blood mononuclear cells to children with cerebral palsy intravenously (title, abstract, pg 2, 1st full paragraph “Intravenous infusion of autologous CBMNC in children with CP represents a novel and safe challenge that may involve a quite different mechanism of action from previous treatment methods”; 23~91 months on pg 3, col. 1, 2nd full paragraph). Intravenous administration described by Lee is “systemic” as required in claim 24.
0.6~15.65x107 CBMCs/kg were infused in one dose (second sentence of “Results”) which is “at least one dose containing at least 2x107 cells/kg” as required in claim 24.
The children were age 23~91 months (pg 3, col. 1, 2nd full paragraph); 23 and 24 months are “10 years old or younger” as required in claim 24.
In Table 1 (pg 4), every “Y” for “Yes” in the chart under “Tx Response” is an indication of “symptoms of CP are treated” as required in claim 24. Specifically, the 23 month old showed “therapeutic responses to autologous cord blood infusions” under the category of PEDI (pediatric evaluation of disability inventory) as indicated by the “Y”. The 24 month old showed “therapeutic responses” under the category of GMFCS as indicated by the “Y”. Lee taught neurological improvement was observed (pg 3, col. 2, 2nd full para). This is all that is required to meet the limitation of “symptoms of CP are treated” in claim 24.
These two children described by Lee MUST inherently have improved “motor function” “at least 12 month after the dose” as required in claim 24 because Lee administered human CBMCs using the exact same total number and dosage used by applicants.
Lee did not teach using allogeneic CBMCs as required in claim 24.
However, Feng administered allogeneic umbilical cord blood stem cells to patients with cerebral palsy intravenously (title, abstract, pg 2, col. 1, 2.2 “Cell infusion and patient monitoring”; pg 2, last partial paragraph for 1-29 years). The children were 1 year old (pg 2, last partial paragraph) which is “10 years old or younger” as required in claim 24. Feng taught “Several preclinic and clinic trials now show that allogeneic UCBSCs have therapeutic effects for CP” (pg 1, 2nd para). The method of Feng MUST inherently result in improved symptoms of CP including motor function for “at least 12 month after the dose” as required in claim 24 because the allogeneic CBMCs and total number of used by Feng are EXACTLY the same as the allogeneic CBMCs and total number of cells used by applicants. Feng administered 2x107 cells/kg over 4-8 injections as follows: Feng administered 2-3x107 cells/dose 4-8 times (pg 2, section 2.2) to patients with an average mean age of 5.85 (pg 3, Table 1). The average weight of a 5 year old female is 17.92 and a 5 year old boy is 18.37 kg. The average weight of a 6 year old female is 19.96 and a 5 year old boy is 20.64 kg. 2-3x107 cells/injection x 4-8 injections is 8x107 – 1.6x108 cells. For a child that is 17.92 kg, that is 8.93x107 cell/kg which is at least 2x107 cells/kg as required in claim 24. Therefore, the total number of cells per kilogram described by Feng was over 2x107 cells/kg.
Thus it would have been obvious to those of ordinary skill in the art at the time of filing to administer CBMCs to a patient with cerebral palsy systemically as described by Lee that are allogeneic as described by Feng. Those of ordinary skill in the art at the time of filing would have been motivated to use allogeneic cells instead of autologous cells because Feng taught allogeneic cells are attractive when children with cerebral palsy have not banked their own umbilical cord blood (pg 3-4, Discussion, paragraph 2) and because Feng taught “allogeneic stem cells may be more beneficial than autologous cells for CP patients” (pg 4, line 6-7).
Response to arguments
Applicants argue Lee did not teach improved motor function for at least 12 months. Applicants’ argue the examiner’s assertion of inherency is unsupported. Applicants’ argument is not persuasive. The phenotype in claim 24 inherently MUST necessarily occur because Lee administered human CBMCs using the exact same total number and dosage used by applicants. This is a scientifically, legally, and logically compelling fact that applicants have not refuted.
Applicants argue only 5 out of 20 patients exhibited improvement beyond what was expected. Applicants’ argument is not persuasive. Claim 24 encompasses any amount of improvement which was exhibited in 5 patients described by Lee. There is nothing in claim 24 that requires symptoms of CP are decreased for at least 12 months. The limitation of “at least 12 months” only applies to improving motor function which inherently MUST occur for reasons set forth above. However, any improvements in CP symptoms over 24 weeks inherently MUST necessarily occur for “at least 12 months” as claimed because Lee administered human CBMCs using the exact same total number and dosage used by applicants. The improvement in CP is consistently present in 5 of the patients.
Applicants argue the examiner’s discussion of the Tx response is misplaced. Applicants argue the examiner’s assertion that the result claimed inherently MUST occur is contradicted by Lee because Lee taught infused cells did not correlate with outcomes. Applicants’ arguments are not persausvie because Lee ameliorated CP symptoms using the exact same dosage and amount of cells claimed.
Applicants argue unexpected results were obtained (pg 11-12). Applicants argue Lee used autologous cells and did not test whether symptoms were decreased after 12 months. Applicants argue the results were not predictable from the cited art “which either employs multi-dose regiments (Feng, Romanov) or demonstrates inconsisten and limited efficacy (Lee)”. Applicants’ arguments are not persuasive. Lee ameliorated CP symptoms using the exact same dosage and amount of cells claimed. Romanov taught a single dose had a therapeutic effect and is not limited to multiple doses. Furthermore, an unexpected results argument is flawed. Such an argument must begin with what was expected. Applicants fail to teach what was expected for Lee regarding decreasing symptoms of CP for 12 months or improving motor function for 12 months. However, claim 24 encompasses decreasing symptoms of CP by any amount for any period of time which is taught by Lee. Claim 24 requires improving motor skills for at least 12 months which is inherent because Lee administered human CBMCs using the exact same total number and dosage used by applicants. This is a scientifically, legally, and logically compelling fact that applicants have not refuted.
Applicants argue the art did not teach a single dose as a predictable alternative; therefore, the rejection is based on an “obvious to try” rationale. Applicants’ argument is unfathomable because Lee and Romanov used a single dose of CBMCs to decrease symptoms of CP. In fact, Lee used a single dose of the same number of CBMCs to decrease symptoms of CP, so applicants’ argument is illogical and legally unsound.
C) Claim 24 remains rejected under 35 U.S.C. 103 as being unpatentable over Yang (J. Transl. Med., 2010, Vol. 8, No. 75, pg 1-6) in view of Lee (J. Transl. Med., 2012, Vol. 10, No. 58, pg 1-11) and supported by “Average height and Weight Babies to Teenagers” (2023).
Yang administered allogeneic CBMCs to patients aged 15-68 (pg 2, 3rd full para) with “degenerative conditions” (title) one of whom had CP (pg 2, Table 1) intravenously in one dose (pg 2, “Cell Processing”; pg 3, “Cell administration”). Each dose was “2 mls of cell suspension containing 1-3x107 cells” via intrathecal or “30 ml intravenous infusion of cell suspension” (pg 3, “Cell Administration”). Assuming each ml contained 1-3x107 cells in each intravenous dose, then 9x108 cells were delivered intravenously to each patient. Assuming the average weight of a 15 year old female is 52.16 kg (“Average height and Weight Babies to Teenagers”), each intravenous and intrathecal single dose administered by Yang was 1.7x107 cells/kg (9x107 cells/52.16 kg). Therapeutic effect evaluations were still in progress – pg 5, last sentence of conclusion. The protocol of Yang MUST inherently have the therapeutic effect in claim 24 because Yang taught a patient of an extremely similar age that was given an extremely similar amount of CBMCs by intravenous delivery (a 15 vs. 10 year old; 1.7x107 vs 2x107 allogeneic CMBCs/kg in one dose intravenously). Moreover, Lee taught a therapeutic effect when 0.6~15.65x107 CBMCs/kg were administered to 23 or 24 month old children with CP intravenously.
Yang taught administering one dose of allogeneic 1.7x107 CBMCs/kg to 15 year old with CP intrathecally and intravenously but did not teach administering one dose of 2x107 CBMCs/kg to children under 10 years of age intravenously as required in claim 24.
However, Lee administered one dose of 0.6~15.65x107 CBMCs/kg (second sentence of “Results”) to children with cerebral palsy intravenously (title, abstract, pg 2, 1st full paragraph “Intravenous infusion of autologous CBMNC in children with CP represents a novel and safe challenge that may involve a quite different mechanism of action from previous treatment methods”; 23~91 months on pg 3, col. 1, 2nd full paragraph). Intravenous administration described by Lee is “systemic” as required in claim 24.
In Table 1 (pg 4), every “Y” for “Yes” in the chart under “Tx Response” is an indication of a therapeutic effect. Specifically, the 23 month old showed “therapeutic responses to autologous cord blood infusions” under the category of PEDI (pediatric evaluation of disability inventory) as indicated by the “Y”. The 24 month old showed “therapeutic responses” under the category of GMFCS as indicated by the “Y”. Lee taught neurological improvement was observed (pg 3, col. 2, 2nd full para). This is a therapeutic effect. These two children under 2 years old infused with one dose of 2x107 CBMCs/kg MUST inherently have the therapeutic effect in claim 24 because Lee administered human CBMCs using the exact same total number, dosage, and route of administration used by applicants.
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to administer 1.7x107 CBMCs /kg to humans 15 years old with CP intrathecally and intravenously as described by Yang by administering one dose of 2x107 cells/kg to patients 10 years of age or younger as described by Lee. Those of ordinary skill in the art at the time of filing would have been motivated to administer 2x107 cells/kg to patients as described by Lee as a matter of optimization. Those of ordinary skill in the art at the time of filing would have been motivated to treat patients under 10 years of age or younger to delay onset of CP.
The combined teachings of Yang and Lee MUST inherently result in the therapeutic effect of claim 24 for reasons set forth above regarding Yang and Lee individually and because the combined teachings of Yang and Lee taught all the limitations claimed.
Yang and Lee taught intravenous administration which is “systemic” as required in claim 25.
Response to arguments
Applicants argue Yang did not teach a single dose of CBMCs as required in claim 24 because Yang taught 4-5 treatments both intrathecal and intravenous. Applicants’ argument is not persuasive. Each dose was “2 mls of cell suspension containing 1-3x107 cells” via intrathecal or “30 ml intravenous infusion of cell suspension” (pg 3, “Cell Administration”). Assuming each ml contained 1-3x107 cells in each intrathecal or intravenous dose, then 9x108 cells were delivered intravenously to each patient. Assuming the average weight of a 15 year old female is 52.16 kg (“Average height and Weight Babies to Teenagers”), each intravenous and intrathecal single dose administered by Yang was 1.7x107 cells/kg (9x107 cells/52.16 kg).
Applicants Yang did not teach any therapeutic effect. Applicants’ argument is not persuasive. Yang taught therapeutic effect evaluations were still in progress – pg 5, last sentence of conclusion, but Yang MUST inherently result in the result claimed because the age of the patients and the number of cells given by Yang were extremely similar to those claimed (15 vs. 10 year old; 1.7x107 vs 2x107 allogeneic CMBCs/kg). The teachings of Yang are otherwise exactly the same as those claimed. Moreover, Lee taught a therapeutic effect occurred when 0.6~15.65x107 CBMCs/kg were administered to 23 or 24 month old children with CP intravenously.
Applicants argue Lee does not cure the deficiencies of Yang because Lee did not measure the therapeutic effect at 12 months as claimed. Applicants’ argument is not persuasive. The two children described by Lee in the age range claimed inherently MUST enjoy the therapeutic effect for “at least 12 month after the dose” as required in claim 24 because Lee administered human CBMCs using the exact same total number and dosage used by applicants and obtained a therapeutic effect.
Applicants argue the examiner’s assertion of optimization is unsupported. Applicants’ argument is not persuasive. Yang taught each intravenous and intrathecal single dose was 1.7x107 cells/kg (9x107 cells/52.16 kg). Changing the dose to 2x107 cells as claimed for optimization was most definitely a specific, valid, and obvious choice based on the art at the time of filing, science, and logic.
Applicants argue the results were unpredictable (pg 14). Applicants’ argument is not persuasive. Yang taught therapeutic effect evaluations were still in progress – pg 5, last sentence of conclusion, but Lee taught a therapeutic effect predictably occurred when 0.6~15.65x107 CBMCs/kg were administered to 23 or 24 month old children with CP intravenously.
D) Claim 24 remains rejected under 35 U.S.C. 103 as being unpatentable over Jensen (Case Reports in Transplantation, 2016, Article ID 1717426, pg 1-9) in view of Feng (Stem Cells, 2015, Article ID 325652, pg 1-7) and Lee (J. Transl. Med., 2012, Vol. 10, No. 58, pg 1-11).
Jensen treated a 4.5 year old human that had CP with autologous CBMCs intravenously (45.8 mL, cryopreserved, TNC 2.53 × 10𝑒8; age 4.5 years on pg 4, col. 1, section 2.4). 2.53 × 10𝑒8 TNCs (pg 4, col. 2, 1st full paragraph) is 1x107 CBMCs/kg (pg 4, 1st full paragraph, line 10). Jensen improved motor function (pg 4, “Outcome).
Jensen did not teach administering 2x107 CBMCs/kg as required in claim 24. However, Lee administered autologous umbilical cord blood mononuclear cells to children with cerebral palsy intravenously (title, abstract, pg 2, 1st full paragraph “Intravenous infusion of autologous CBMNC in children with CP represents a novel and safe challenge that may involve a quite different mechanism of action from previous treatment methods”; 23~91 months on pg 3, col. 1, 2nd full paragraph). Intravenous administration described by Lee is “systemic” as required in claim 24. 0.6~15.65x107 CBMCs/kg were infused in one dose (second sentence of “Results”) which is “at least one dose containing at least 2x107 cells/kg” as required in claim 24. The children were age 23~91 months (pg 3, col. 1, 2nd full paragraph); 23 and 24 months are “10 years old or younger” as required in claim 24. In Table 1 (pg 4), every “Y” for “Yes” in the chart under “Tx Response” is an indication of “symptoms of CP are treated” as required in claim 24. Specifically, the 23 month old showed “therapeutic responses to autologous cord blood infusions” under the category of PEDI (pediatric evaluation of disability inventory) as indicated by the “Y”. The 24 month old showed “therapeutic responses” under the category of GMFCS as indicated by the “Y”. Lee taught neurological improvement was observed (pg 3, col. 2, 2nd full para). This is all that is required to meet the limitation of “symptoms of CP are treated” in claim 24. These two children described by Lee MUST inherently have improved “motor function” “at least 12 month after the dose” as required in claim 24 because Lee administered human CBMCs using the exact same total number and dosage used by applicants. Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to administer CBMCs to children with CP as described by Jensen using 2x107 CBMCs/kg as described by Lee. Those of ordinary skill in the art at the time of filing would have been motivated to increase the number of cells to optimize the therapeutic effect.
Jensen did not teach administering allogeneic CBMCs as required in claim 24. However, Feng administered allogeneic CBMCs to patients with CP intravenously (title, abstract, pg 2, col. 1, 2.2 “Cell infusion and patient monitoring”; pg 2, last partial paragraph for 1-29 years). Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to administer at least 2x107 cells/kg CBMCs to pediatric CP patients and obtain a therapeutic effect as described by Jensen using allogeneic CBMCs described by Feng. Those of ordinary skill in the art at the time of filing would have been motivated to use allogeneic cells instead of autologous cells because Feng taught allogeneic cells are attractive when children with cerebral palsy have not banked their own umbilical cord blood (Discussion, paragraph 2).
Jensen did not teach the patient was 10 years old or younger as required in claim 24. However, Feng administered allogeneic umbilical CBMCs to 1 year old patients with CP (pg 2, last partial paragraph), and Lee treated 23 and 24 patients that have CP with CBMCs injected intravenously (pg 3, col. 1, 2nd full paragraph). Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to administer at least 2x107 cells/kg CBMCs to pediatric CP patients and obtain a therapeutic effect as described by Jensen in a patient that is 10 years old or younger as described by Feng and Lee. Those of ordinary skill in the art at the time of filing would have been motivated to treat patients 10 years old or younger to delay onset of serious disease and prevent death.
Therapeutic effect
The method of Jensen as written MUST inherently result in the therapeutic effect “at least 12 month after the dose” as required in claim 24 because the CBMCs, route of administration, and total number of allogeneic CMBCs used by Feng are EXACTLY the same type of cells, route of administration, dosage schedule, and number of cells described by applicants as being part of the invention. Jensen taught the patient had a “remarkable recovery” (abstract). Therefore, the protocol of Jensen without modification also MUST inherently result in the therapeutic effect claimed.
Jensen taught obtaining a therapeutic effect. Table 1 of Lee taught a therapeutic effect. The combined teachings of Jensen, Feng, and Lee MUST inherently result in the therapeutic effect in claim 24 because two of the references taught therapeutic effects and because the combined references taught all the limitations claimed.
Response to arguments
Applicants argue Jensen says “causality is impossible to establish” with the observed outcome. Applicants argue Jensen only uses one patient who underwent “active rehabilitation” without controls. Therefore, applicants conclude the Examiner’s inherency conclusion cannot be a valid (pg 15). Applicants’ argument is not persuasive. Jensen merely says the cause, i.e. the mechanism of action, of the therapeutic effect cannot be determined. In no way does Jensen question whether the therapeutic effect will occur when administering CMBCs.
Applicants argue Jensen only used approximately 1x107 cells/kg (section 2.4 Autologous cord blood cell transplantation, pg 4). Applicants’ argument is not persuasive because the combined teachings of Jensen, Feng, and Lee taught using the number of CBMCs claimed.
Applicants argue the Examiner has not provided logic for inherency. Applicants’ argument is not persuasive. Jensen improved motor function (pg 4, “Outcome). The combined teachings of Jensen, Feng, and Lee also MUST inherently result in the therapeutic effect claimed because they teach the EXACT same type of cells, route of administration, dosage schedule, and number of cells claimed. This is all the logic that is required.
Applicants argue the results were unpredictable (pg 16). Applicants’ argument is not persuasive. Jensen taught obtaining a therapeutic effect. Table 1 of Lee taught a therapeutic effect. The combined teachings of Jensen, Feng, and Lee MUST inherently result in the therapeutic effect in claim 24 because two of the references taught therapeutic effects and because the combined references taught all the limitations claimed.
E) Claim 24 remains rejected under 35 U.S.C. 103 as being unpatentable over Meier (Pediatric Res., 2006, Vol. 59, pg 244-249) in view of Feng (Stem Cells, 2015, Article ID 325652, pg 1-7) as supported by Rumajogee (Front. Neurology, 2016, Vol. 7, No. 57, pg 1-20).
Meier administered human CBMCs to rats with cerebral hypoxic-ischemic damage caused by ligation of the left common carotid artery followed by systemic hypoxia (pg 244, col. 2, “hUCB-derived mononuclear cells”; pg 245, col. 1, “Cerebral Ischemia”, “Experimental Protocol”). The CBMCs were administered intraperitoneally (pg 245, col. 1, 4th full para, line 7). The hypoxic-ischemic rat has “cerebral palsy” as required in claim 24 because Rumajogee taught this rat is a model of cerebral palsy (abstract).
Meier did not teach administering at least 2x107 allogeneic CBMCs/kg to a human with CP who is 10 years old or less as required in claim 24.
However, it was well-known to administer allogeneic CBMCs to human patients with CP who are 1 year old intravenously as described by Feng (title, abstract, pg 2, col. 1, 2.2 “Cell infusion and patient monitoring”; pg 2, last partial paragraph for 1-29 years; pg 2, last partial paragraph).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to administer human CBMCs to mammal that has CP as described by Meier and administering allogeneic CBMCs to human patients with CP who are 1 year old intravenously as described by Feng. Those of ordinary skill in the art at the time of filing would have been motivated to use allogeneic CBMCs instead of autologous CBMCs because Feng taught allogeneic cells are attractive when children with cerebral palsy have not banked their own umbilical cord blood (Discussion, paragraph 2). Those of ordinary skill in the art at the time of filing would have been motivated to treat patients under 10 years of age to delay progression of CP.
Feng administered 2x107 CBMCs/kg over 4-8 injections for reasons set forth in rejection A) above. Feng did not administer one dose of 2x107 cells/kg as required in claim 24. However, it would have been obvious to do administer the cells all at once systemically to decrease visits to the clinic. Those of ordinary skill in the art at the time of filing would have been motivated to reduce the number of doses to one dose to improve efficiency. Modifying the dosage was well within the purview of the ordinary practitioner at the time of filing as evidenced by Feng. Those of ordinary skill in the art at the time of filing would have been motivated to administer one dose of 2x107 cells/kg systemically to patients as required in claim 24 as a matter of optimization.
Therapeutic effect
The method of Feng alone MUST inherently result in the therapeutic effect in claim 24 because the allogeneic CBMCs, route of administration, and total number of allogeneic CMBCs used by Feng are EXACTLY the same type of cell, route of administration, and number of cells as those used by applicants. Feng taught “Several preclinic and clinic trials now show that allogeneic UCBSCs have therapeutic effects for CP” (pg 1, 2nd para). Therefore, the protocol of Feng without modification MUST inherently result in the therapeutic effect claimed.
Modifying the protocol of Feng to one dose also MUST inherently result in the therapeutic effect claimed because the type of cell, route of administration, dosage schedule, and number of cells are EXACTLY those used by applicants and claimed.
Intravenous administration described by Feng is “systemic” as required in claim 25.
Response to arguments
Applicants argue Meier did not teach the species, dosage or age in claim 24. Applicants’ argument is not persuasive. The combined teachings of Meier and Feng taught all the limitations claimed for reasons set forth above.
Applicants argue there was no reasonable expectation of success in applying the teachings of Meier to a human with CP under 10 years of age and using one dose of 2x107 CBMCs/kg. Applicants’ argument is not persuasive. It was well-known to administer allogeneic CBMCs to human patients with CP who are 1 year old intravenously as described by Feng (title, abstract, pg 2, col. 1, 2.2 “Cell infusion and patient monitoring”; pg 2, last partial paragraph for 1-29 years; pg 2, last partial paragraph). While Feng did not administer one dose of 2x107 cells/kg as required in claim 24, it was obvious to do so for reasons set forth above. Since the animal described by Meier was a model of CP in humans, there was a reasonable expectation of successfully obtaining the therapeutic effect claimed.
Conclusion
No claim allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Inquiry concerning this communication or earlier communications from the examiner should be directed to Michael C. Wilson who can normally be reached at the office on Monday through Friday from 9:30 am to 6:00 pm at 571-272-0738.
Patent applicants with problems or questions regarding electronic images that can be viewed in the Patent Application Information Retrieval system (PAIR) can now contact the USPTO’s Patent Electronic Business Center (Patent EBC) for assistance. Representatives are available to answer your questions daily from 6 am to midnight (EST). The toll free number is (866) 217-9197. When calling please have your application serial or patent number, the type of document you are having an image problem with, the number of pages and the specific nature of the problem. The Patent Electronic Business Center will notify applicants of the resolution of the problem within 5-7 business days. Applicants can also check PAIR to confirm that the problem has been corrected. The USPTO’s Patent Electronic Business Center is a complete service center supporting all patent business on the Internet. The USPTO’s PAIR system provides Internet-based access to patent application status and history information. It also enables applicants to view the scanned images of their own application file folder(s) as well as general patent information available to the public.
For all other customer support, please call the USPTO Call Center (UCC) at 800-786-9199.
If attempts to reach the examiner are unsuccessful, the examiner's supervisor, Tracy Vivlemore, can be reached on 571-272-2914.
The official fax number for this Group is (571) 273-8300.
Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
Prosecution Insights