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 .
DETAILED ACTION
The amendment to the claims filed after non-final office action on March 26, 2026 is acknowledged. Claims 1-11, 15-17, 20-23 were amended and claims 1-23 are pending in the instant application. The restriction was deemed proper and made final previous office action.
Claims 12-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-11, 15-23 are examined on the merits of this office action.
Withdrawn Rejections/Objections
The objections to claims 2-3, 9-11, 15-16, 20, 22-23 are withdrawn in view of amendment of the claims filed March 26, 2026.
The rejection of claims 1-11, 15-23 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in view of amendment of the claims to remove variants from the claim filed March 26, 2026.
The rejection of claims 4-11 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in view of amendment of the claims field March 26, 2026.
The rejection of claims 4-11 and 19-23 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is withdrawn in view of amendment of the claims field March 26, 2026.
The rejection of claim(s) 1-5, 9-11 under 35 U.S.C. 102(a)(1) as being anticipated by Shah (US20170281732 A1) is withdrawn in view of amendment of the claims field March 26, 2026.
The rejection of claims 1-11, 15-23 on the ground of nonstatutory double patenting as being unpatentable over claims 2-16, 18, 20-21 of copending Application No. 17/665360 (reference application) n view of Shah (US20170281732 A1) and Dessy (Cureus. 2017 Dec 7;9(12):e19220 is withdrawn in view of abandonment of the copending application.
Maintained/Revised Rejections
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) 1-11, 15-23 remain rejected under 35 U.S.C. 103 as being unpatentable over Shah (US20170281732 A1) in view of Shah* (US20180071367 A1) and Dessy (Cureus. 2017 Dec 7;9(12):e19220).*All references cited in the previous office action.
Regarding claim 1, Shah teaches treating mild brain injury or concussion with ghrelin or a variant thereof (see abstract, claim 1). Shah discloses administration within 8-72 hours, with follow up dosing for 1-14 days after injury (see paragraphs 0026, 0028). Shah specifies repeated administration (1, 2, 3 or more follow up dosages in 1-14 days)( see paragraph 0026).
Regarding administering to a patient with a “sustained mTBI”, a sustained mTBI refers to a mild traumatic brain injury that continues to cause symptoms/impairments. Shah teaches that the present disclosure also provides for a method of reducing the incidence or severity of mTBI or the symptoms or sequelae of a mild brain injury or concussion in a subject, comprising administering to the subject an effective amount of a ghrelin variant, a composition comprising a ghrelin variant or a therapeutic product as described herein, thereby reducing the incidence or severity of the mTBI or concussion. Shah additionally teaches “Such methods can be used for immediate treatment of the injury, the symptoms thereof and the sequelae, and also can be used to prevent or reduce long term or chronic sequelae” (See paragraph 0029). Shah teaches cumulative injury damage (paragraph 0004), long term deterioration of cognitive and motor skills (paragraph 0005), and prevention of CTE and memory loss (paragraph 0046-0048). The above show treatment of sustained mTBI, defined as mild traumatic brain injury that continues to cause symptoms.
Shah further teaches monitoring patients suffering loss of cognitive or motor skills due to mTBI over time and states that decreasing ghrelin levels create an increased need for intervention (paragraph 0250). Such teachings further demonstrate that Shah contemplates treatment and therapeutic intervention responsive to progression or persistence or symptoms beyond immediate acute injury period. Although Shah discloses preferred embodiments involving administration within 72 hours after injury, Shah is not limited solely to acute phase treatment. Shah expressly teaches treatment of symptoms, sequelae, and “long term or chronic sequelae” associated with mTBI (paragraph 0029). A person of ordinary skill in the art would have understood such sequelae and chronic sequelae to persist beyond the immediate post injury period and therefore would have reasonably understood Shah to contemplate treatment of patients experiencing ongoing or persistent symptoms after the acute phase or injury.
Further, Shah does not criticize, discredit or otherwise discourage treatment initiated after 72 hours. Rather, Shah broadly teaches treatment over a post injury therapeutic period extending 1-14 days after injury, including treatment directed to persistent symptoms and chronic neurological effects associated with mTBI. Accordingly, a person of ordinary skill in the art would have reasonably understood that initiation timing could vary depending on patient presentation, persistence or progression of symptoms, and clinical considerations, including initiation of treatment more than 3 days after mTBI in patients continuing to experience symptoms or sequelae following injury. In view of Shah’s express teachings regarding persistent symptoms, chronic sequelae, and ongoing monitoring of patients over time, initiating treatment more than 3 days after injury would have represented no more than the predictable use of Shah’s disclosed ghrelin therapy according to its established neuroprotective and anti-inflammatory functions (see KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007), MPEP2141(III).
Shah teaches a broader range of ghrelin (10 ng/kg-10 mg/kg) with an example of one 2 ug/kg (see paragraph 0739). Shah is silent to about 80 ug/kg/day or 40 ug/kg twice per day (instant claims 15-16).
Shah* teaches cognitive impairments caused by mTBI comprising administering ghrelin (see claims 1-2). Shah* teaches a range of dosing (10 ng/kg-10 mg/kg) and varying doses including 10 ug two times (see paragraph 0063).
Regarding the claimed dosage of about 80ug/kg/day, Shah and Shah* both teach therapeutically effective ghrelin dosage ranges encompassing ug/kg administration, repeated dosing regimens, and dose titration. Selection of a therapeutically effective dose within the disclosed ranges would have been within the ordinary skill in the art based on routine clinical considerations, including therapeutic response, symptom severity, pharmacokinetic considerations, and patient specific factors, with a reasonable expectation of success. Applicant has not provided evidence demonstrating criticality or unexpected results associated with claimed dosage. The precise dose, frequency and duration of administration are matters of routine optimization that would have been well within the skill of the ordinary artisan. As established in In re Aller (see MPEP 2144.05), discovering optimum or workable ranges of a result effective variable involves only routine optimization. Thus, it would have been obvious to optimize dosing parameters, including selection of 40, 80 ug/kg, or BID administration, based on patient response and pharmacokinetic considerations, with a reasonable expectation of success.
Therefore, it would have been obvious to a person of ordinary skill in the art to administer ghrelin at a dose of about 80 ug/kg/day and to initiate treatment more than 3 days after mTBI in a patient experiencing persistent, progressive, or chronic symptoms or sequelae following injury.
Regarding claim 2, Shah discloses continuing ghrelin administration until recovery and resolution of post concussive symptoms (see paragraphs 0009, 0740, method of treating mild brain injury or concussion in a patient suffering from said mBI or concussion, wherein the method continues until the patient is symptom free).
Regarding claim 3, Shah discloses wherein the ghrelin is administered as a pharmaceutical formulation (paragraphs0031, 0038, 0289).
Regarding claim 4, Shah discloses sterile injectable formulation (see paragraph 0038, 0289).
Regarding claim 5, Shah teaches administration via a patch (0038 ,0358).
Regarding claims 6-8, Shah teaches repeated dosing for 1-14 days after mBI (see paragraphs 0026, 0028). The precise dose, frequency and duration of administration are matters of routine optimization that would have been well within the skill of the ordinary artisan. As established in In re Aller (see MPEP 2144.05), discovering optimum or workable ranges of a result effective variable involves only routine optimization. Thus, it would have been obvious to optimize dosing parameters, including duration of treatment, based on patient response and pharmacokinetic considerations, with a reasonable expectation of success.
Regarding claim 9, Shah discloses single daily dosing regimens (see paragraphs 0028, 0032).
Regarding claim 10, Shah discloses parenteral and subcutaneous routes, including “EpiPens” (see paragraph 0032, 0038).
Regarding claim 11, Shah discloses continuing administration until recovery is achieved (see paragraphs 026, 0028, 0036, 0288, paragraph 0740).
Regarding claim 15, Shah disclose a method for mitigating one or more symptoms of mTBI (paragraphs 0009, 0029), method of treating a mild brain injury or concussion in a patient suffering from said mTBI or concussion, wherein said treatment includes symptoms thereof (paragraph 0081) comprising selecting a patient having mTBI due to an injury and the one or more symptoms of mTBI at least 7 days after the injury (see paragraph 0026, 0051), the method includes selecting or identifying a subject that has suffered a mTBI or concussion and administering to the subject ghrelin or variant thereof dosages within 1-14 days after the injury); b. administering ghrelin or a variant thereof to the patient for a period of time, wherein ghrelin or the variant thereof is administered at a dose (paragraph 0038, ghrelin variant can be administered in two doses and the ghrelin variant can be administered at a dosage from 10 ng/kg per day to 10 mg/kg).
Shah further teaches treatment of symptoms, sequelae, and chronic sequelae associated with mTBI, as well as monitoring progression of cognitive or motor impairment over time with intervention as needed (paragraphs 0029, 0250). Such teachings would have suggested treatment of patients continuing to experience symptoms following the acute phase of injury.
Shah teaches a broader range of ghrelin (10 ng/kg-10mg/kg) with an example of one 2 ug/kg dose (see paragraph 0739). Shah is silent about 80 ug/kg/day or 40 ug/kg twice per day (instant claims 15-16).
Shah* teaches cognitive impairments caused by mTBI comprising administering ghrelin (see claims 1-2). Shah* teaches a range of dosing (10 ng/kg-10mg/kg) and varying doses including 10 ug two times (see paragraph 0063).
Regarding the claimed dosage of about 80 ug/kg/day or about 40 ug/kg twice per day, Shah and Shah* both teach therapeutically effective ghrelin dosage ranges encompassing ug/kg administration, repeated dosing regimens, and dose titration. Selection of a therapeutically effective dose within the disclosed ranges would have been within the ordinary skill in the art based on routine clinical considerations, including therapeutic response, symptom severity, pharmacokinetic considerations, and patient specific factors, with a reasonable expectation of success. Applicant has not provided evidence demonstrating criticality or unexpected results associated with the claimed dosage.
The precise dose, frequency and duration of administration are matters of routine optimization that would have been well within the skill of the ordinary artisan. As established in MPEP 2144.05, discovering optimum or workable ranges of a result effective variable involves only routine optimization. Thus, it would have been obvious to optimize dosing parameters, including selection of 40, 50 ug/kg, or BID administration, based on patient response and pharmacokinetic considerations, with a reasonable expectation of success.
Regarding claims 17-18, Shah teaches administering follow up doses for up to 14 days (see paragraph 0026). Nevertheless, determining exact treatment duration (up to 14 days or about 14 days) is a result effective variable (duration directly affects therapeutic effect) and would be obvious to optimize.
Regarding claims 19, 21, Shah teaches monitoring symptoms of brain injury during and after treatment with ghrelin (see paragraph 0043, 0054, 0740).
Regarding claim 20, Shah teaches establishing a baseline prior to dosing (see for example paragraph 0740). Nevertheless, evaluation prior to administering is obvious because a person of ordinary skill in the art would have recognized the necessity of baseline assessment to compare outcomes.
Regarding claims 19-22 Shah teaches monitoring symptoms of brain injury during and after treatment with ghrelin (see paragraph 0043, 0054, 0740). Specific evaluation intervals (3, 7, 10, 14 days etc…)are routine variations of Shah’s disclosed monitoring within hours/days of dosing (see paragraph 0740). Selection of exact timepoints is an obvious optimization.
Regarding claim 23, Shah is silent to evaluation using the tools found in instant claim 23. However, Dessy teaches “ The most commonly used tools for evaluating individuals with concussion are the Post-Concussion Symptom Scale (PCSS), Standard Assessment of Concussion (SAC), Standard Concussion Assessment Tool (SCAT3), and the most recognized computerized neurocognitive test, the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT)” (see abstract). Thus, use of PCS, QOLIBRI, PGAS, or BrainCheck represents selection of standard validate tools known in the art for evaluating mBI recovery. Shat teaches evaluation of neurological, cognitive, and functional outcomes, and POSA would have found it obvious to employ recognized instruments for this purpose.
Response to Applicant’s Arguments
Applicant respectfully disagree for at least the following reasons. As an initial matter, none of the cited art references, alone or in combination teach or suggest all of the claimed elements. Additionally, the Office has failed to demonstrate or provide evidence of any teaching or suggestion that would motivate the skilled artisan to select the specific initiation and dosage of ghrelin treatment recited by the instant claims from the very broad disclosure of Shah I or Shah II. There are many choices and selections that would have to be made from the broad disclosure of the cited references, which does not provide any teaching or suggestion to make the specific selections and choices from the many options. In fact, Shah I provides explicit teaching away from choosing to initiate ghrelin treatment more than 3 days after injury. Second, even assuming the skilled artisan would make the specific selections (which the Applicant does not concede), the Office still has failed to demonstrate that the skilled artisan would have had a reasonable expectation of success that the specific timing of initiation and dosing of ghrelin would be effective.
As the Examiner is aware, a claimed species encompassed by a genus disclosed in the prior art does not per se render the claimed species as being obvious. MPEP §2144.08 clearly states that the fact that a claimed species is encompassed in a genus disclosed in the prior art does not per se create a primafacie case of obviousness. For example, the MPEP states that "[u]se of per se rules by Office personnel is improper for determining whether claimed subject matter would have been obvious under 35 U.S.C. 103. See, e.g., In re Brouwer, 77 F.3d 422, 425, 37 USPQ2d 1663, 16668 (Fed. Cir. 1996); In re Ochiai, 71 F.3d 1565, 1572, 37 USPQ2d 1127, 1133 (Fed. Cir. 1995); In re Baird, 16 F.3d 380, 382, 29 USPQ2d 1550, 1552 (Fed. Cir. 1994). The fact that a claimed species or subgenus is encompassed by a prior art genus is not sufficient by itself to establish a primafacie case of obviousness. In re Baird, 16 F.3d 380, 382, 29 USPQ2d 1550, 1552 (Fed. Cir. 1994) ("The fact that a claimed compound may be encompassed by a disclosed generic formula does not by itself render that compound obvious."); In re Jones, 958 F.2d 347, 350, 21 USPQ2d 1941, 1943 (Fed. Cir. 1992) (Federal Circuit has "declineld] to extract from Merck [& Co. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989)] the rule that... regardless of how broad, a disclosure of a chemical genus renders obvious any species that happens to fall within it.")" Emphasis added. See MPEP § 2144.08.
In addition, the MPEP states that, if a "reference's disclosed range is so broad as to encompass a very large number of possible distinct compositions, this might present a situation analogous to the obviousness of a species when the prior art broadly discloses a genus." See MPEP 2144.05(I), citing In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003); emphasis added; also citing In re Baird, 16 F.3d 380, 29 USPQ2d 1550 (Fed. Cir. 1994); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992); MPEP § 2144.08. Here, the Office has failed to provide evidence that Shah I and Shah II, alone or in combination, would motivate the skilled artisan to select both the specific timing of the initiation of treatment (i.e., more than 3 days after injury) and the specific dosage of ghrelin (i.e., about 80 pg/kg per day) as recited by the instant claims. For example, neither Shah I nor Shah II disclose a method having all of the limitations of the instant claims, in which the treatment is initiated more than 3 days after mTBI and wherein the ghrelin is administered at a dose of about 80 pg/kg per day. Shah I teaches a range of 10 ng/kg to 10 mg/kg Shah I discloses an extraordinarily broad ghrelin dosage range-10 ng/kg to 10 mg/kg, spanning six orders of magnitude-and provides no guidance that would direct the skilled artisan to the instantly claimed 80 pg/kg per day. Even if one were to assume, arguendo, that the skilled artisan would select only integer microgram-per-kilogram doses (and Shah I provides no teaching or rationale to motivate such narrowing), this range encompasses at least 10,000 discrete pg/kg values between 0.01 pg/kg and 10,000 pg/kg. Nothing in Shah I teaches or even suggests a dose of about 80 pg/kg, and the sheer number of possible selections underscores that Shah I fails to teach or suggest the claimed dose. In fact, Shah I is merely an invitation for further research on dosing parameters. For example, Example 7 of Shah I teaches the skilled artisan to perform a dose titration across the large range of its disclosure to calculate the "minimum efficacious dose." See Shah I at para. [0763]-[0764]. But there is no teaching or suggestion within Shah I to select the instantly claimed dose. Accordingly, selecting the particular value of 80 pg/kg from this vast, undifferentiated spectrum cannot reasonably be characterized as "routine optimization" but instead reflects hindsight reconstruction of Applicant's own teachings.
Similarly, there is no teaching in the cited references that the treatment should be initiated more than 3 days after injury. For example, Shah I teaches that the administration occurs within not more than 72 hours of the injury. See Shah I at claim 32. In addition, Shah I teaches that "[f]ollowing a diagnosis of mild brain injury, such as a concussion, ghrelin or a ghrelin variant can be administered to the patient, preferably in not more than 72 hours initially." Emphasis added. Id. at para. [0252]. Furthermore, Shah teaches methods including "administering to a patient suffering from a mild brain injury or concussion a therapeutically effective amount of ghrelin within a certain period (e.g., 72 hours) of the mild brain injury or concussion." Emphasis added. Id. at para. [0353]. The skilled artisan would readily appreciate that Shah I only teaches administering the ghrelin within 72 hours and explicitly teaches that the treatment should not be initiated more than 72 hours. Furthermore, Example 9 of Shah I is merely an invitation for further research regarding the maximum effective treatment window. Id. at para. [0768]. However, the skilled artisan would appreciate that all the suggested treatment initiations occur within the 72 hours immediately following injury. Id. Shah II cannot remedy this defect of Shah I because Shah II also teaches the ghrelin treatment should be initiated within 72 hours of injury. See Shah II at para. [0192], [0283], and claims 34-36.
The skilled artisan would understand that Shah I teaches reactive oxygen burst was increased in animals following mild brain injury (mTBI) compared to controls. See Shah I at para. [0731]. These measurements were taken within 2-8 hours of injury. Id. at para. [0730]. Shah I teaches that mTBI or concussion causes "subtle metabolic changes within the brain, specifically an increase oxidative stress and overproduction of reactive oxygen species (ROS) which in turn can damage neuroconnectivity, lead to neuronal damage and encephalopathic changes with recurrent injury." Id. at para. [0732]. Shah I further teaches that ghrelin increases uncoupling protein-2 (UCP-2) in the brain of mice. Id. Shah I concludes that the ghrelin-induced increase in UCP-2 decreases ROS and the subsequent damage caused to neurons following injury. Id. at para. [0733]. The skilled artisan would appreciate that Shah I teaches ghrelin treatment within a narrow window following mTBI (i.e., acute phase), whereas the instant application is directed to a treatment more than 3 days following injury (i.e., sub-acute phase). The skilled artisan would appreciate that without intervention within the first 24 hours, a patient experiencing mTBI will already have increased inflammation and ROS production, which lead to further neuronal injury.
In addition, the instant application teaches that sustained mTBI is a condition in which the symptoms of a mTBI has not resolved after several days to weeks and discloses methods and compositions for use in treating sustained mTBI. Specification at para. [0028]-[0029]. Furthermore, the specification teaches that "[u]nlike patients treated immediately after the mTBI, patients suffering from a sustained mTBI have allowed the biological cascade of adverse events in the brain to continue unabated. Such events include untreated inflammation in the brain due, for example, to metabolic derangement, neuronal damage, or inflammation associated with overproduction of reactive oxygen species (ROS)." Id. at para. [0030]. Thus, the skilled artisan would have no reasonable expectation of success in treating a patient with the specific dose of ghrelin (i.e., 80 pg/kg per day) outside the maximum effective treatment window (i.e., more than 3 days after the injury) as recited by the instant claims. Furthermore, the Office has failed to provide any evidence to support their assertions that the skilled artisan would select these two elements out of the broad disclosure of Shah I and Shahn II. Finally, the Office has failed to provide evidence that the skilled artisan would have been motivated to ignore the explicit teachings of Shah I and Shah II regarding that the treatment must be initiated within 3 days, to arrive at the instant claims.
For at least the reasons set forth above, Applicant respectfully submit that the pending claims are inventive over the combination of cited references and request withdrawal of the rejection under § 103.
Applicant’s arguments have been fully considered but not found persuasive. Applicant argues that Sha and Shah* fail to teach or suggest initiating ghrelin treatment more than 3 days after injury and further argues that the references teach away from delayed administration because the references emphasize administration within 72 hours of injury. The arguments are not found persuasive. While Shah discloses preferred embodiments involving administration within 72 hours of injury (e.g. paragraphs 0252, 0353), Shah is not limited to immediate acute phase treatment. Rather, Shah expressly teaches treatment of symptoms, sequelae, short term sequelae, long term sequelae, and chronic sequelae, associated with mTBI or concussion. See paragraph 0029 (“methods can be used for immediate treatment of the injury, the symptoms thereof and the sequelae, and also can be used to prevent or reduce long term or chronic sequelae”).
Shah further teaches monitoring patients over time for progression of cognitive or motor impairment associated with mTBI. Paragraph 0250 teaches that “a patient suffering loss of cognitive or motor skills due to mTBI and, in particular, repetitive mTBI, can be monitored for therapy or progression of such skills,” and further teaches that “as the ghrelin levels decrease, there will be an increased need for intervention.” This disclosure reasonably suggests continued or later therapeutic intervention responsive to persistent or progressive symptomology rather than treatment limited solely to the initial acute injury period.
Further, Shah teaches treatment directed to reducing the severity or duration of one or more symptoms of mTBI or concussion and teaches use in conjunction with diagnostic or monitoring protocols. See paragraph 0252. Such disclosures would have suggested to a person of ordinary skill in the art that treatment timing could vary depending upon patient presentation, persistence of symptoms, progression of impairment, and therapeutic response.
In view of Shah’s express teachings regarding persistent symptoms, chronic sequelae, and ongoing monitoring of patients over time, initiating treatment more than 3 days after injury would have represented no more than the predictable use of Shah’s disclosed ghrelin therapy according to its established neuroprotective and anti-inflammatory functions (see KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007), MPEP2141(III)
Applicant argues that Shah teaches away from delayed treatment because Shah discusses reactive oxygen species (ROS) generation shortly after injury. However, a reference teaches away only when it criticizes, discredits, or otherwise discourages the claimed approach. Shah does not state that treatment initiated after 72 hours would be ineffective, contraindicated, or inoperable. Instead, Shah expressly contemplates treatment of long term or chronic sequelae and monitoring patients over time for progressive impairment and intervention needs. These disclosures are inconsistent with Applicant’s characterization that Shah is limited exclusively to acute phase administration.
Applicant additionally argues that the Office improperly relies upon routine optimization from a broad dosage range. The argument is not persuasive. Shah and Shah* both teach therapeutically effective ug/kg dosing ranges, repeated administration, and dose titration. Selection of a therapeutically effective dose and treatment timing based upon symptom persistence, therapeutic response and clinical considerations would have been within ordinary level of skill in the art.
Further, Applicant has not directed the Office to evidence demonstrating criticality or unexpected results associated with either the claimed dosage or the claimed initiation timing relative to the broad therapeutic teachings of Shah and Shah*.
Applicant’s arguments regarding hindsight are not persuasive because the Office’s rejection is based on express teachings in Shah itself, rather than impermissible reconstruction using Applicant’s disclosure as a roadmap. Shah expressly teaches treatment of mTBI symptoms, long-term or chronic sequelae, monitoring patients over time, and increasing intervention where symptoms persist or ghrelin levels decrease. See Shah at paras. [0029], [0250]. Shah further teaches therapeutic administration over a post-injury treatment period extending up to 14 days after injury. Thus, the Office’s conclusion that a person of ordinary skill in the art would have considered initiating or continuing treatment beyond the acute post-injury phase is grounded in the prior art’s own recognition that mTBI symptoms and neurological sequelae may persist over time.
The rejection does not rely on Applicant’s specification to modify Shah, but instead relies on the predictable application of Shah’s expressly disclosed ghrelin therapy to patients exhibiting persistent symptoms or chronic sequelae following injury. KSR makes clear that an obviousness analysis need not identify an explicit teaching directed to the precise claimed combination where the claimed modification represents no more than the predictable use of prior art elements according to their established functions. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007) (see MPEP 2141 (III)).
Further, as stated above, Shah does not teach away from treatment initiated more than 72 hours after injury. While Shah discloses preferred embodiments involving administration within 72 hours, Shah also broadly teaches treatment of persistent symptoms and chronic sequelae associated with mTBI and continued therapeutic monitoring over time. A disclosure of preferred timing does not criticize, discredit, or otherwise discourage alternative treatment timing directed to ongoing symptoms. Therefore, the Office’s conclusion is based on the express teachings and reasonable inferences from Shah itself rather than hindsight reconstruction. Accordingly, the rejection under 35 U.S.C. 103 is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-11, 15-23 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-7, 9, 11, 18, 20-23, 31-32, 43, 50-51, 53-54 of copending Application No. 19/109418 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method for mitigating one or more symptoms of a mild traumatic brain injury (mTBI) for a patient diagnosed with a sustained mTBI which method comprises administering to the patient an effective amount of ghrelin over multiple consecutive days after diagnosis, wherein the ghrelin administration is initiated more than 3 days after the mTBI, and wherein the ghrelin is administered at a dose of about 80 ug/kg per day” (see claim 1). The instant application further claims “ghrelin administration is continued until the patient’s symptoms become asymptomatic” (Claim 2); pharmaceutical composition with sterile aqueous solution for injection (claims 3-4);transdermal patch (claim 5); administration maintenance for at last 3, 5, 7 days after diagnosis of mTBI; single dose (claim 9); subcutaneous injection (Claim 10); patient able to resume activities (claim 11); treating symptoms of mTBI at least 7 days after injury (Claim 15); 50 ug/kg or split dose (claims 15-16); administering up to 14 days (Claims 17-18); monitoring symptoms before and after administration (claims 19-22); and doing so via one or more of PCSS, QOLIBRI, PGAS, and/or BrainCheck (claim 23).
Co-pending AN19/109418 claims “A method for mitigating one or more symptoms of a mild traumatic brain injury (mTBI) for a patient diagnosed with a sustained mTBI which method comprises administering to the patient an effective amount of ghrelin or a variant thereof over multiple consecutive days after diagnosis, wherein the one or more symptoms are improved by at least 20% compared to baseline within about 40 days after initial administration of ghrelin or a variant thereof” (Claim 1). The copending application further claims improvement of symptoms (monitored from 10-30 days after) via BrainCheck (See claims 1-6). The copending application further claims administering until symptoms are gone (claim 7); a pharmaceutical formulation of the ghrelin (claim 8); sterile injectable aqueous solution (Claim ); transdermal patch (Claim 10); administration for at least 3, 5, 40 days (Claims 11-13); single dose (claim 14); subcutaneous injection (Claim 16); administering until patient can resume normal activities (Claim 17); 80 ug/kg a day (Claim 20); 40 ug/kg twice (claim 22); administering up to 14 days (claim 24); evaluation of symptoms pre and post administration and on scheduled basis (Claims 23-28); administering at least 7 days after the injury (Claim 21).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
Applicant respectfully disagrees with the double patenting rejections and requests that these rejections be held in abeyance until allowable subject matter in the present application has been identified.
Applicant’s arguments regarding the nonstatutory double patenting rejection have been considered but are not persuasive. The rejection is maintained because the pending claims are not patentably distinct from the claims of co-pending Application No. 19/109418 as previously set forth. Applicants request to hold the rejection in abeyance is not adopted at this time.
Claims 1-11, 15-23 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 9119832 B2 in view of Shah (US20170281732 A1) and Dessy (Cureus. 2017 Dec 7;9(12):e19220.
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method for mitigating one or more symptoms of a mild traumatic brain injury (mTBI) for a patient diagnosed with a sustained mTBI which method comprises administering to the patient an effective amount of ghrelin over multiple consecutive days after diagnosis, wherein the ghrelin administration is initiated more than 3 days after the mTBI, and wherein the ghrelin is administered at a dose of about 80 ug/kg per day” (see claim 1). The instant application further claims “ghrelin administration is continued until the patient’s symptoms become asymptomatic” (Claim 2); pharmaceutical composition with sterile aqueous solution for injection (claims 3-4);transdermal patch (claim 5); administration maintenance for at last 3, 5, 7 days after diagnosis of mTBI; single dose (claim 9); subcutaneous injection (Claim 10); patient able to resume activities (claim 11); treating symptoms of mTBI at least 7 days after injury (Claim 15); 50 ug/kg or split dose (claims 15-16); administering up to 14 days (Claims 17-18); monitoring symptoms before and after administration (claims 19-22); and doing so via one or more of PCSS, QOLIBRI, PGAS, and/or BrainCheck (claim 23).
US Patent No. ‘832 claims “A method of treating concussion in a subject, comprising administering to the subject a therapeutically effective amount of ghrelin, thereby treating the concussion, wherein the ghrelin is the sole active agent” (Claim 1). US Patent No. ‘832 further claims wherein the ghrelin is administered after a the mild brain injury (same as mTBI0 (claims 8-10), 10ng/kg-10 mg/kg per day (claim 11).
US Patent No. ‘832 is silent to administering to a patient diagnosed as having a sustained mTBI; treating until asymptomatic, transdermal patch, administration for at least 3 up to 7 days; administrating more than 3 days after, subcutaneous injection, dosing of 80 ug/kg or split in half; treatment up to 14 days, assessing symptoms at various time points of treatment (i.e. concussion symptoms with mBI via PCSS, BrainCheck et…) at multiple time points and also at baseline.
However, Shah teaches treating mild brain injury or concussion with ghrelin or a variant thereof (see abstract, claim 1). Shah discloses administration within 8-72 hours, with follow up dosing for 1-14 days after injury (see paragraphs 0026, 0028). Shah specifies repeated administration (1, 2, 3 or more follow up dosages in 1-14 days)( see paragraph 0026). Regarding administering to a patient with a “sustained mTBI”, a sustained mTBI refers to a mild traumatic brain injury that continues to cause symptoms/impairments. Shah teaches The present disclosure also provides for a method of reducing the incidence or severity of mBI or the symptoms or sequelae of a mild brain injury or concussion in a subject, comprising administering to the subject an effective amount of a ghrelin variant, a composition comprising a ghrelin variant or a therapeutic product as described herein, thereby reducing the incidence or severity of the mBI or concussion. Shah additionally teaches “Such methods can be used for immediate treatment of the injury, the symptoms thereof and the sequelae, and also can be used to prevent or reduce long term or chronic sequelae” (See paragraph 0029). Shah teaches cumulative injury damage (paragraph 0004), long term deterioration of cognitive and motor skills (paragraph 0005), and prevention of CTE and memory loss (paragraph 0046-0048). The above show treatment of sustained mTBI, defined as mild traumatic brain injury that continues to cause symptoms. Shah discloses continuing ghrelin administration until recovery and resolution of post concussive symptoms (see paragraphs 0009, 0740, method of treating mild brain injury or concussion in a patient suffering from said mBI or concussion, wherein the method continues until the patient is symptom free). Shah discloses wherein the ghrelin is administered as a pharmaceutical formulation (paragraphs0031, 0038, 0289). Shah discloses sterile injectable formulation (see paragraph 0038, 0289). Shah teaches administration via a patch (0038 ,0358). Shah teaches repeated dosing for 1-14 days after mBI (see paragraphs 0026, 0028). The precise dose, frequency and duration of administration are matters of routine optimization that would have been well within the skill of the ordinary artisan. As established in In re Aller (see MPEP 2144.05), discovering optimum or workable ranges of a result effective variable involves only routine optimization. Thus, it would have been obvious to optimize dosing parameters, including duration of treatment, based on patient response and pharmacokinetic considerations, with a reasonable expectation of success. Shah discloses single daily dosing regimens (see paragraphs 0028, 0032). Shah discloses parenteral and subcutaneous routes, including “EpiPens” (see paragraph 0032, 0038). Shah discloses continuing administration until recovery is achieved (see paragraphs 026, 0028, 0036, 0288, paragraph 0740).
Shah teaches administering follow up doses for up to 14 days (see paragraph 0026). Nevertheless, determining exact treatment duration (up to 14 days or about 14 days) is a result effective variable (duration directly affects therapeutic effect) and would be obvious to optimize.
Shah teaches monitoring symptoms of brain injury during and after treatment with ghrelin (see paragraph 0043, 0054, 0740).
Shah teaches establishing a baseline prior to dosing (see for example paragraph 0740). Nevertheless, evaluation prior to administering is obvious because a person of ordinary skill in the art would have recognized the necessity of baseline assessment to compare outcomes. Shah teaches monitoring symptoms of brain injury during and after treatment with ghrelin (see paragraph 0043, 0054, 0740). Specific evaluation intervals (3, 7, 10, 14 days etc…)are routine variations of Shah’s disclosed monitoring within hours/days of dosing (see paragraph 0740). Selection of exact timepoints is an obvious optimization.
Regarding claim 23, Dessy teaches “ The most commonly used tools for evaluating individuals with concussion are the Post-Concussion Symptom Scale (PCSS), Standard Assessment of Concussion (SAC), Standard Concussion Assessment Tool (SCAT3), and the most recognized computerized neurocognitive test, the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT)” (see abstract). Thus, use of PCS, QOLIBRI, PGAS, or BrainCheck represents selection of standard validate tools known in the art for evaluating mBI recovery. It would have been obvious to evaluate neurological, cognitive, and functional outcomes of the treatment, and POSA would have found it obvious to employ recognized instruments for this purpose.
It would have been obvious to a person of ordinary skill in the art at the time of the invention to modify the methods of US Patent No. ‘832, which claims treating concussion and mTBI with ghrelin to also encompass treatment of patients with sustained mTBI, in view of Shah. Shah teaches administering ghrelin to subjects with mTBI or concussion, including repeated administration for 1-14 days and until symptoms resolve, and emphasizes prevention of or reduction of chronic sequelae. In light of these teachings, a person of ordinary skill would have been motivated to apply the same ghrelin therapy claimed in US Patent No. ‘832 to the recognized subgroup of sustained mTBI patients, with a reasonable expectation that the same neuroprotective mechanisms would mitigate symptoms regardless of duration.
Regarding administration more than 3 days, Although Shah discloses preferred embodiments involving administration within 72 hours after injury, Shah is not limited solely to acute phase treatment. Shah expressly teaches treatment of symptoms, sequelae, and “long term or chronic sequelae” associated with mTBI (paragraph 0029). A person of ordinary skill in the art would have understood such sequelae and chronic sequelae to persist beyond the immediate post injury period and therefore would have reasonably understood Shah to contemplate treatment of patients experiencing ongoing or persistent symptoms after the acute phase or injury.
Further, Shah does not criticize, discredit or otherwise discourage treatment initiated after 72 hours. Rather, Shah broadly teaches treatment over a post injury therapeutic period extending 1-14 days after injury, including treatment directed to persistent symptoms and chronic neurological effects associated with mTBI. Accordingly, a person of ordinary skill in the art would have reasonably understood that initiation timing could vary depending on patient presentation, persistence or progression of symptoms, and clinical considerations, including initiation of treatment more than 3 days after mTBI in patients continuing to experience symptoms or sequelae following injury.
Response to Applicant’s Arguments
Applicant respectfully disagrees with the double patenting rejections and requests that these rejections be held in abeyance until allowable subject matter in the present application has been identified.
Applicant’s arguments regarding the nonstatutory double patenting rejection have been considered but are not persuasive. The rejection is maintained because the pending claims are not patentably distinct from the claims of US Patent NO. ‘832 in view of Shah and Dessy as previously set forth. Applicants request to hold the rejection in abeyance is not adopted at this time.
Claims 1-11, 15-23 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 10105416 B2 in view of Shah (US20170281732 A1) and Dessy (Cureus. 2017 Dec 7;9(12):e19220).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method for mitigating one or more symptoms of a mild traumatic brain injury (mTBI) for a patient diagnosed with a sustained mTBI which method comprises administering to the patient an effective amount of ghrelin over multiple consecutive days after diagnosis, wherein the ghrelin administration is initiated more than 3 days after the mTBI, and wherein the ghrelin is administered at a dose of about 80 ug/kg per day” (see claim 1). The instant application further claims “ghrelin administration is continued until the patient’s symptoms become asymptomatic” (Claim 2); pharmaceutical composition with sterile aqueous solution for injection (claims 3-4);transdermal patch (claim 5); administration maintenance for at last 3, 5, 7 days after diagnosis of mTBI; single dose (claim 9); subcutaneous injection (Claim 10); patient able to resume activities (claim 11); treating symptoms of mTBI at least 7 days after injury (Claim 15); 50 ug/kg or split dose (claims 15-16); administering up to 14 days (Claims 17-18); monitoring symptoms before and after administration (claims 19-22); and doing so via one or more of PCSS, QOLIBRI, PGAS, and/or BrainCheck (claim 23).
US Patent No. ‘416 claims “ A method of treating mild traumatic brain injury (mTBI) in a subject, comprising administering to the subject a therapeutically effective amount of ghrelin, thereby treating the mTBI, wherein a selective androgen receptor modulator is not administered” (see claim 1). US Patent No. ‘416 further claims administered 24 hours after mTBI (claim 9); wherein ghrelin is administered at a dosage from 10 ng/kg per day to 10 mg/kg per day; wherein ghrelin is administered in a single dose (claim 22).
US Patent No. ‘416 is silent to administering to a patient diagnosed as having a sustained mTBI; treating until asymptomatic, transdermal patch, administration for at least 3 up to 7 days; subcutaneous injection, dosing of 80 ug/kg or split in half; treatment up to 14 days, assessing symptoms at various time points of treatment (i.e. concussion symptoms with mBI via PCSS, BrainCheck et…) at multiple time points and also at baseline; administration initiated more than 3 days after the mTBI.
However, Shah teaches treating mild brain injury or concussion with ghrelin or a variant thereof (see abstract, claim 1). See full teachings of Shah and Dessy in the above rejection.
It would have been obvious to a person of ordinary skill in the art at the time of the invention to modify the methods of US Patent No. ‘416, which claims treating concussion and mTBI with ghrelin to also encompass treatment of patients with sustained mTBI, in view of Shah. Shah teaches administering ghrelin to subjects with mTBI or concussion, including repeated administration for 1-14 days and until symptoms resolve, and emphasizes prevention of or reduction of chronic sequelae. In light of these teachings, a person of ordinary skill would have been motivated to apply the same ghrelin therapy claimed in US Patent No. ‘416 to the recognized subgroup of sustained mTBI patients, with a reasonable expectation that the same neuroprotective mechanisms would mitigate symptoms regardless of duration.
Regarding administration more than 3 days, Although Shah discloses preferred embodiments involving administration within 72 hours after injury, Shah is not limited solely to acute phase treatment. Shah expressly teaches treatment of symptoms, sequelae, and “long term or chronic sequelae” associated with mTBI (paragraph 0029). A person of ordinary skill in the art would have understood such sequelae and chronic sequelae to persist beyond the immediate post injury period and therefore would have reasonably understood Shah to contemplate treatment of patients experiencing ongoing or persistent symptoms after the acute phase or injury.
Further, Shah does not criticize, discredit or otherwise discourage treatment initiated after 72 hours. Rather, Shah broadly teaches treatment over a post injury therapeutic period extending 1-14 days after injury, including treatment directed to persistent symptoms and chronic neurological effects associated with mTBI. Accordingly, a person of ordinary skill in the art would have reasonably understood that initiation timing could vary depending on patient presentation, persistence or progression of symptoms, and clinical considerations, including initiation of treatment more than 3 days after mTBI in patients continuing to experience symptoms or sequelae following injury.
Response to Applicant’s Arguments
Applicant respectfully disagrees with the double patenting rejections and requests that these rejections be held in abeyance until allowable subject matter in the present application has been identified.
Applicant’s arguments regarding the nonstatutory double patenting rejection have been considered but are not persuasive. The rejection is maintained because the pending claims are not patentably distinct from the claims of US Patent NO. ‘416 in view of Shah and Dessy as previously set forth. Applicants request to hold the rejection in abeyance is not adopted at this time.
Claims 1-11, 15-23 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11241483 B2 in view of Shah (US20170281732 A1) and Dessy (Cureus. 2017 Dec 7;9(12):e19220).*References cited previously.
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method for mitigating one or more symptoms of a mild traumatic brain injury (mTBI) for a patient diagnosed with a sustained mTBI which method comprises administering to the patient an effective amount of ghrelin over multiple consecutive days after diagnosis, wherein the ghrelin administration is initiated more than 3 days after the mTBI, and wherein the ghrelin is administered at a dose of about 80 ug/kg per day” (see claim 1). The instant application further claims “ghrelin administration is continued until the patient’s symptoms become asymptomatic” (Claim 2); pharmaceutical composition with sterile aqueous solution for injection (claims 3-4);transdermal patch (claim 5); administration maintenance for at last 3, 5, 7 days after diagnosis of mTBI; single dose (claim 9); subcutaneous injection (Claim 10); patient able to resume activities (claim 11); treating symptoms of mTBI at least 7 days after injury (Claim 15); 50 ug/kg or split dose (claims 15-16); administering up to 14 days (Claims 17-18); monitoring symptoms before and after administration (claims 19-22); and doing so via one or more of PCSS, QOLIBRI, PGAS, and/or BrainCheck (claim 23).
US Patent No. ‘483 claims “ A method for treating mild traumatic brain injury in a subject, comprising administering to the subject between about 1.0 μg per kg bodyweight (μg/kg) to about 0.1 mg/kg of ghrelin per day” (see claim 1). US Patent No. ‘483 further claims treating chronic symptoms of mTBI, multiple injections; wherein ghrelin is administered in a single dose (claim 11).
US Patent No. ’483 is silent to administering to a patient diagnosed as having a sustained mTBI; treating until asymptomatic, transdermal patch, administration for at least 3 up to 7 days; subcutaneous injection, dosing of 80 ug/kg or split in half; treatment up to 14 days, assessing symptoms at various time points of treatment (i.e. concussion symptoms with mBI via PCSS, BrainCheck et…) at multiple time points and also at baseline.
However, Shah teaches treating mild brain injury or concussion with ghrelin or a variant thereof (see abstract, claim 1). See full teachings of Shah and Dessy in the above rejection.
It would have been obvious to a person of ordinary skill in the art at the time of the invention to modify the methods of US Patent No. ’483, which claims treating concussion and mTBI with ghrelin to also encompass treatment of patients with sustained mTBI, in view of Shah. Shah teaches administering ghrelin to subjects with mTBI or concussion, including repeated administration for 1-14 days and until symptoms resolve, and emphasizes prevention of or reduction of chronic sequelae. In light of these teachings, a person of ordinary skill would have been motivated to apply the same ghrelin therapy claimed in US Patent No. ’483 to the recognized subgroup of sustained mTBI patients, with a reasonable expectation that the same neuroprotective mechanisms would mitigate symptoms regardless of duration.
Regarding administration more than 3 days, Although Shah discloses preferred embodiments involving administration within 72 hours after injury, Shah is not limited solely to acute phase treatment. Shah expressly teaches treatment of symptoms, sequelae, and “long term or chronic sequelae” associated with mTBI (paragraph 0029). A person of ordinary skill in the art would have understood such sequelae and chronic sequelae to persist beyond the immediate post injury period and therefore would have reasonably understood Shah to contemplate treatment of patients experiencing ongoing or persistent symptoms after the acute phase or injury.
Further, Shah does not criticize, discredit or otherwise discourage treatment initiated after 72 hours. Rather, Shah broadly teaches treatment over a post injury therapeutic period extending 1-14 days after injury, including treatment directed to persistent symptoms and chronic neurological effects associated with mTBI. Accordingly, a person of ordinary skill in the art would have reasonably understood that initiation timing could vary depending on patient presentation, persistence or progression of symptoms, and clinical considerations, including initiation of treatment more than 3 days after mTBI in patients continuing to experience symptoms or sequelae following injury.
Response to Applicant’s Arguments
Applicant respectfully disagrees with the double patenting rejections and requests that these rejections be held in abeyance until allowable subject matter in the present application has been identified.
Applicant’s arguments regarding the nonstatutory double patenting rejection have been considered but are not persuasive. The rejection is maintained because the pending claims are not patentably distinct from the claims of US Patent NO. ‘483 in view of Shah and Dessy as previously set forth. Applicants request to hold the rejection in abeyance is not adopted at this time.
Claims 1-11, 15-23 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 10617740 B2 in view of Shah (US20170281732 A1) and Dessy (Cureus. 2017 Dec 7;9(12):e19220).*all references cited previously.
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method for mitigating one or more symptoms of a mild traumatic brain injury (mTBI) for a patient diagnosed with a sustained mTBI which method comprises administering to the patient an effective amount of ghrelin over multiple consecutive days after diagnosis, wherein the ghrelin administration is initiated more than 3 days after the mTBI, and wherein the ghrelin is administered at a dose of about 80 ug/kg per day” (see claim 1). The instant application further claims “ghrelin administration is continued until the patient’s symptoms become asymptomatic” (Claim 2); pharmaceutical composition with sterile aqueous solution for injection (claims 3-4);transdermal patch (claim 5); administration maintenance for at last 3, 5, 7 days after diagnosis of mTBI; single dose (claim 9); subcutaneous injection (Claim 10); patient able to resume activities (claim 11); treating symptoms of mTBI at least 7 days after injury (Claim 15); 50 ug/kg or split dose (claims 15-16); administering up to 14 days (Claims 17-18); monitoring symptoms before and after administration (claims 19-22); and doing so via one or more of PCSS, QOLIBRI, PGAS, and/or BrainCheck (claim 23).
US Patent No. ‘740 claims “A method of treating mild traumatic brain injury (mTBI) in a subject, comprising identifying a subject having a Glasgow Coma Scale score between 13 and 15 and administering to the subject a therapeutically effective amount of ghrelin, thereby treating the mTBI” (Claim 1). US Patent No. ‘483 further claims administered within not more than about 24 hours of the mTBI (Claim 10); single dose (claim 13); dosage of 10 ng/kg to 10 mg/kg per day (claim 14); chronic symptoms of mTBI (Claim 20); pharmaceutical formulation and subcutaneous administration (claims 22-25).
US Patent No. ’740 is silent to administering to a patient diagnosed as having a sustained mTBI; treating until asymptomatic, transdermal patch, administration for at least 3 up to 7 days; subcutaneous injection, dosing of 80 ug/kg or split in half; treatment up to 14 days, assessing symptoms at various time points of treatment (i.e. concussion symptoms with mBI via PCSS, BrainCheck et…) at multiple time points and also at baseline.
However, Shah teaches treating mild brain injury or concussion with ghrelin or a variant thereof (see abstract, claim 1). See full teachings of Shah and Dessy in the above rejection.
It would have been obvious to a person of ordinary skill in the art at the time of the invention to modify the methods of US Patent No. ’740, which claims treating concussion and mTBI with ghrelin to also encompass treatment of patients with sustained mTBI, in view of Shah. Shah teaches administering ghrelin to subjects with mTBI or concussion, including repeated administration for 1-14 days and until symptoms resolve, and emphasizes prevention of or reduction of chronic sequelae. In light of these teachings, a person of ordinary skill would have been motivated to apply the same ghrelin therapy claimed in US Patent No. ’740 to the recognized subgroup of sustained mTBI patients, with a reasonable expectation that the same neuroprotective mechanisms would mitigate symptoms regardless of duration.
Regarding administration more than 3 days, Although Shah discloses preferred embodiments involving administration within 72 hours after injury, Shah is not limited solely to acute phase treatment. Shah expressly teaches treatment of symptoms, sequelae, and “long term or chronic sequelae” associated with mTBI (paragraph 0029). A person of ordinary skill in the art would have understood such sequelae and chronic sequelae to persist beyond the immediate post injury period and therefore would have reasonably understood Shah to contemplate treatment of patients experiencing ongoing or persistent symptoms after the acute phase or injury.
Further, Shah does not criticize, discredit or otherwise discourage treatment initiated after 72 hours. Rather, Shah broadly teaches treatment over a post injury therapeutic period extending 1-14 days after injury, including treatment directed to persistent symptoms and chronic neurological effects associated with mTBI. Accordingly, a person of ordinary skill in the art would have reasonably understood that initiation timing could vary depending on patient presentation, persistence or progression of symptoms, and clinical considerations, including initiation of treatment more than 3 days after mTBI in patients continuing to experience symptoms or sequelae following injury.
Response to Applicant’s Arguments
Applicant respectfully disagrees with the double patenting rejections and requests that these rejections be held in abeyance until allowable subject matter in the present application has been identified.
Applicant’s arguments regarding the nonstatutory double patenting rejection have been considered but are not persuasive. The rejection is maintained because the pending claims are not patentably distinct from the claims of US Patent NO. ‘740 in view of Shah and Dessy as previously set forth. Applicants request to hold the rejection in abeyance is not adopted at this time.
New Objection
Claim 15 is objected to for the following informality: the periods after “a” and “b” should be removed. Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995). Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i) (see MPEP 608.01(m)).
New Rejections
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 6-8 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.
Claim 6 recites that “the administration of ghrelin…is maintained for a period of at least 3 days after diagnosis of a sustained mTBI.” It is unclear whether this limitation refers to the duration of administration itself or instead defines a time window after diagnosis during which administration occurs. Furthermore, because claim 1 recites initiation of administration “more than 3 days after the mTBI”, the temporal relationship between initiation of treatment and the “maintained for” limitation is unclear.
Claims 7 and 8 depend from claim 6 and similarly recite that administration “is maintained for a period of at least 5 days” and “at least 7 days after diagnosis”, respectively. Accordingly, these claims inherit the same ambiguity and are indefinite for the same reasons.
Conclusion
No claims are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 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, Lianko Garyu can be reached at 571-270-7367. 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.
/ERINNE R DABKOWSKI/Examiner, Art Unit 1654
Prosecution Insights