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 .
Status of the Claims
Claims 20, 23-24, 29-30, 32-36 and 38 are pending in the instant application and subject to examination herein.
Claim Rejections - 35 USC § 103 – Withdrawn
The prior rejection of claims 20-22, 25-27, 29-30, 32-33, 35-36 and 38 under 35 U.S.C. 103 as being unpatentable over El-Radhi (El-Radhi, et al.; Clinical Manual of Fever in Children, Chapter 5 – “Fever in Common Infectious Diseases”, pp85-140; Springer, 2018), in view of Déciga-Campos (Déciga-Campos and Ortiz-Andrade; Drug Development Research, v76, pp228-334; 2015)1 and Hesselink (Hesselink, et al.; International Journal of Inflammation, v2013, Article ID 151028, pp1-8; 2013) is withdrawn in response to Applicant’s amendment of claims 20, 29-30, 32 and 35-36 and cancellation of claims 21-22 and 25-27.
The prior rejection of claims 20-22, 24-27, 29-30, 32-33, 35-36 and 38 under 35 U.S.C. 103 as being unpatentable over El-Radhi in view of Déciga-Campos and Hesselink and further in view of Gabrielsson (Gabrielsson, British Journal of Clinical Pharmacology, v82, pp932-942; 2016) is withdrawn in response to Applicant’s amendment of claims 20, 24, 29-30, 32 and 35-36 and cancellation of claims 21-22 and 25-27.
The prior rejection of claims 20-23, 25-30, 32-36 and 38 under 35 U.S.C. 103 as being unpatentable over El-Radhi in view of Déciga-Campos and Hesselink and further in view of Temple (Temple et al.; Clinical Therapeutics, v35, pp1361-1375; 2013) is withdrawn in response to Applicant’s amendment of claims 20, 23, 29-30, 32, 34 and 35-36 and cancellation of claims 21-22 and 25-28.
Applicant has traversed these rejections with the following rationales:
None of the cited references, individually, specifically disclose or suggest using a paracetamol/PEA combination at the claimed doses for treating fever, let alone using a combination for treating fever while reducing side-effects associated with paracetamol consumption;
El-Radhi discourages the administration of a combination of antipyretics, and therefore a person of ordinary skill in the art would not seek a second agent to combine with paracetamol or ibuprofen as a treatment for fever;
Deciga-Campos teaches the combination of paracetamol and PEA specifically for hyperalgesia (sensitivity to pain) in diabetic rats and proposes the combination as a potential therapy for diabetic patients, rather than teaching the general applicability of the combination for pain, broadly, or for pain associated to fever, specifically, and is therefore irreconcilable with the teachings of El-Radhi;
Temple and Gabrielsson regard administration of paracetamol and PEA, respectively, each in isolation and do not provide a motivation to combine these agents, and therefore do not cure the deficiencies of El-Radhi, Hesselink and Deciga-Campos.
Applicant’s arguments have been considered, but are not found persuasive, for the following reasons:
El-Radhi does inherently suggest drug replacement as a treatment strategy, because the combined administration of paracetamol and ibuprofen is a replacement of part of the dose of paracetamol by substitution with ibuprofen. A person of ordinary skill in the art would have a reasonable expectation of success in further substituting ibuprofen for another safe and efficacious pain reliever, which would comply with El-Radhi’s discouragement of combining antipyretics, since PEA is a known analgesic/anti-inflammatory agent (per the teaching of Hesselink) but is not reported in the prior art to be a direct antipyretic agent;
While Hesselink establishes that palmitoylethanolamine (PEA) is a known treatment for pain and fever, a person of ordinary skill in the art would not need Hesselink to specifically articulate the substitution of PEA for ibuprofen in a combination treatment of pain together with paracetamol, because the simple substitution of one known element for another to obtain predictable results is a known rationale for obviousness – see MPEP § 2141.III.B;
Deciga-Campos utilizes a model of measurable chronic pain in rats wherein diabetes is induced in rats via treatment with streptozotocin, thereby rendering the rats hyperalgesic (i.e., very sensitive), and teaches that diabetic neuropathy represents a particular challenge in pain treatment because an observed low efficacy of antidepressants, anticonvulsants, opiods and non-steroidal anti-inflammatory drugs (NSAIDS) in diabetic patients. While Deciga-Campos makes a specific appeal in the Abstract, as noted by Applicant, to the relevance of the findings of the research to pain therapy in neuropathic diabetic patients, the body of Deciga-Campos’ work contains multiple indications to the broader relevance of the study results that show that the synergy of paracetamol and PEA is not specifically limited to diabetic neuropathy:
Deciga-Campos states that the antihyperalgesic inducing effects of PEA observed in the study are consistent with results of previous studies based on other models of pain, including mechanical and thermal hyperalgesia in chronic inflammation tests wherein the hyperalgesia was induced by Freund’s adjuvant or carrageenan, and also consistent with results of studies wherein hyperalgesia and allodynia were induced by chronic constriction injury of the sciatic nerve in mice (page 232);
Deciga-Campos reviews the anti-nociceptive mechanisms of PEA and paracetamol to propose means by which the observed synergy of the study results may arise that do not depend from the diabetic state, including the differential and complementary effects of PEA and paracetamol on cannabinoid receptors CB2 and CB1, respectively (page 233);
Deciga-Campos concludes the study with the observation that “The inhibition of the central COX pathway can reduce inflammatory pain by enhancing CB-induced antinociception. Thus, combined administration of cannabinoids with COX inhibitors may be therapeutically useful in the treatment of inflammatory pain.” Thus, while Deciga-Campos specifically recommends the combination of paracetamol and PEA to the treatment of diabetic neuropathy, a person of ordinary skill in the art would recognize that the synergy proposed for the combination should have broad applicability to pain treatment.
Claim Rejections - 35 USC § 103 – Necessitated by Amendments
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.
Claims 20, 23-24, 29-30, 32-36 and 38 unpatentable over El-Radhi in view of Barkin, Hesselink, Deciga-Campos, Gabriellson and Temple.
Claims 20, 23-24, 29-30, 32-36 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over El-Radhi (El-Radhi, et al.; Clinical Manual of Fever in Children, pp85-140 and 220-241; Springer, 2018), in view of Barkin (Barkin, R. L.; American Journal of Therapeutics, v8, pp433-442; 2001), Hesselink (Hesselink, et al.; International Journal of Inflammation, v2013, Article ID 151028, pp1-8; 2013), Déciga-Campos (Déciga-Campos and Ortiz-Andrade; Drug Development Research, v76, pp228-334; 2015)2, Gabrielsson (Gabrielsson, British Journal of Clinical Pharmacology, v82, pp932-942; 2016) and Temple (Temple et al.; Clinical Therapeutics, v35, pp1361-1375; 2013).
By way of background, patients who become infected with viral infections, for example upper respiratory tract infections (URTIs), deal with symptoms of the body’s response to the virus, such as congestion, as well as other symptoms such as fever, pain (headache, myalgia), and general discomfort (malaise). There are many approaches in the art that can be used to directly reduce viral load, reduce airway congestion, and/or treat symptoms such as fever or pain via pharmaceutical means.
Claim 20 is drawn to a method of treating fever comprising administering:
Paracetamol (in a dosage within 0.5-4000mg); and
Palmitoylethanolamide (in a dosage within 50-5000mg)
El-Radhi teaches the treatment of fever in children, including children having an upper respiratory tract infection (URTI), including such treatment comprising administering an analgesic-antipyretic medication, for example paracetamol and/or ibuprofen (page 87). El-Radhi teaches that fever enhances body’s immunity against infection, and antipyretics may negatively affect the outcome of the illness. Therefore antipyretics should only be given for symptomatic children, such as discomfort, and not for fever per se (page 87). El-Radhi teaches that “Febrile children often experience discomfort, headaches and myalgia resulting in reduced activity and causing anxiety to the parents. Antipyretics by being analgesics lead to an improvement in the children’s level of activity and alertness,” (page 229) and that “The principal benefit of the antipyretic drug is to make children more comfortable; and that is because the antipyretic drug also has analgesic property” and that antipyretics should be used sparingly (page 220). Regarding paracetamol and ibuprofen as analgesic-antipyretics, El-Radhi teaches that excessive paracetamol can worsen asthma, and that ibuprofen is not recommended in children with dehydration (page 87), and that ibuprofen is more expensive and has more side-effects than paracetamol (page 226). El-Radhi teaches that the most commonly prescribed antipyretic is paracetamol, and the second most commonly prescribed is a combination of paracetamol and ibuprofen, and that URTIs are the most common reason for the administration of antipyretics (page 87). For paracetamol alone, El-Radhi teaches a dosing regimen of 10-15 mg/kg at 4-6 hour intervals (page 87). While El-Radhi does not discourage the practice of combining analgesics, El-Radhi does discourage the practice of alternating or combining antipyretics as there is no scientific evidence to support this practice (pages 87 and 225), and, as noted above, since both paracetamol and ibuprofen are analgesic-antipyretic medications, their pairing constitutes a combination of antipyretics.
While El-Radhi does not advocate for substituting an analgesic, for example palmitoylethanoloamide (PEA), for either paracetamol or ibuprofen in a combination treatment of the discomfort/myalgia associated with fever in a child, and El-Radhi does not advocate a specific fixed dose of paracetamol and/or palmitoylethanolamide, a person of ordinary skill in the art would have a reasonable expectation of success in combining palmitoylethanolamide (PEA), a known analgesic but not antipyretic medication, with paracetamol, an analgesic-antipyretic, in doses within the ranges disclosed in claim 20 for the treatment of pediatric fever, including fever experienced in associating with a URTI, for the following reasons:
It was known in the art that improved pain relief can be demonstrated, and adverse effects minimized, by multimodal analgesic combinations to improve pain treatment and in some instances, such combinations have a heterogenous pharmacologic sparing effect, per the teaching of Barkin;
It was known in the art that PEA is an analgesic, anti-inflammatory agent that can be safely administered to children, per the teaching of Hesselink;
It was known in the art that combination therapy of palmitoylethanolamide with paracetamol provides a synergistic analgesic effect allowing lower dose(s) of paracetamol to achieve pain relief, per the teaching of Déciga-Campos;
Safe and efficacious dosages of paracetamol and PEA are result-effective variables, and determining safe and efficacious dose of paracetamol and/or of PEA was known in the art per the teachings of Temple and Gabrielsson, respectively.
Barkin teaches that Pain is a complex sensory and emotional process that remains neither fully understood nor uniformly defined. The pain process involves both central and peripheral mechanisms, with numerous substance and receptors responsible for the transmission and modulation of the pain response. With so many pathways and mechanisms involved, the neurobiology of pain suggests that several targets or processes must be addressed simultaneously for pain relief to be most effective. Given the multiple mechanisms responsible for each etiology of pain, combining analgesics with different mechanisms of action is often recommended for the relief of acute and chronic pain (page 433). Barkin further teaches that decreasing dose-related adverse effects is another important rationale for combining analgesics owing to the use of lower doses of the component drugs, and that combining individual analgesics may also maximize pain relief by capitalizing on the pharmacokinetic profiles (page 434). Finally, Barkin teaches that fixed-combination analgesics are widely used and prescribed in the United States (page 434), including common analgesics such as aspirin, ibuprofen and acetaminophen (paracetamol) with each other, or with codeine and its derivatives, with caffeine, and with any of many other analgesic agents (pp437-440).
Hesselink teaches PEA has anti-inflammatory and analgesic properties, stemming from its effect of reducing mast cell migration and degranulation and reduction in the pathological overactivation of mast cells, from its ability to reduce the activity of proinflammatory enzymes, and its direct affinity for multiple pain-related receptors, including cannabinoid receptors GPR55, GPR119, the vanillinoid receptor TRPV1 and the nuclear peroxisome proliferator-activated receptor-a (PPAR-a) (page 5). Hesselink teaches that palmitoylethanolamide (PEA) has been shown, across multiple clinical trials, to be an effective agent for the treatment of flu and respiratory infections. In the period of 1969-1979, the results of a total of 5 trials in adults and one trial in children were published. All of these were double-blinded and placebo-controlled, without relevant side effects (page 4). In particular, the trial involving children included doses of 300 mg, twice daily.
Déciga-Campos teaches that the combination administration of paracetamol (acetaminophen) and PEA can effectively treat pain in subjects at dosage below the corresponding treatments of either PEA or paracetamol alone (page 230 – Results, third paragraph; page 231 – Figure 3A-C; page 233 – second paragraph). Déciga-Campos explains the synergy between the PEA and analgesic compounds (see paragraph bridging pages 228 and 229), and discloses an injectable formulation:
“Groups of six rats each received increasing concentrations of PEA (1, 3, 10, 30, and 100 mcg/paw), acetaminophen (3, 10, 30, 100 and 300 mcg/paw) or a PEA/acetaminophen combination (8, 16, 32, 64.4, 128.8 mcg/paw). All drugs were administered 15 min before the formalin tests.” 3
Deciga-Campos states that the antihyperalgesic inducing effects of PEA observed in the study are consistent with results of previous studies based on other models of pain, including mechanical and thermal hyperalgesia in chronic inflammation tests wherein the hyperalgesia was induced by Freund’s adjuvant or carrageenan, and also consistent with results of studies wherein hyperalgesia and allodynia were induced by chronic constriction injury of the sciatic nerve in mice (page 232). Deciga-Campos reviews the anti-nociceptive mechanisms of PEA and paracetamol to propose means by which the observed synergy of the study results may arise that do not depend from the diabetic state, including the differential and complementary effects of PEA and paracetamol on cannabinoid receptors CB2 and CB1, respectively (page 233). Deciga-Campos concludes the study with the observation that “The inhibition of the central COX pathway can reduce inflammatory pain by enhancing CB-induced antinociception. Thus, combined administration of cannabinoids with COX inhibitors may be therapeutically useful in the treatment of inflammatory pain.” Thus, while Deciga-Campos specifically recommends the combination of paracetamol and PEA to the treatment of diabetic neuropathy, a person of ordinary skill in the art would recognize that the synergy proposed for the combination should have broad applicability to pain treatment.
Temple reviews published and unpublished pediatric antipyretic data to provide a critical assessment of the 10-15 mg/kg oral dosing recommendation originally provided in 1983 and the current (as of 2013) pediatric oral dosing schedules for acetaminophen (paracetamol). Temple reviews 13 unpublished clinical trials and 40 published clinical trials that each included at least one oral formulation (page 1362). The trials included dosages from 40 mg up to 480 mg, according to a given patient’s weight, such that the dose by weight was generally kept within the range of 10-15 mg/kg (Table II, page 1363). Results of the review support the recommended 10-15 mg/kg oral dose and demonstrate that the age and weight schedules for over-the-counter acetaminophen proposed in 1983 remain appropriate.
Gabrielsson provides a review article on the use of oral PEA for treating pain. Table 1 summarizes a number of clinical studies that provide daily dosages of PEA in amounts as low as 300 mg up to amounts of 1200 mg . Certain of the studies summarized in Table 1 administer PEA as the sole active for treating pain (see Gabrielsson refs 41, 49, 54, and 57), while other studies listed in Table 1 use PEA, including at amount of 800 mg, in conjunction with an additional analgesic such as transpolydatin (see Gabrielsson refs 44 and 52) and pregabalin (see Gabrielsson ref 55). These values largely encompass the discreet values claimed in claim 24. Gabrielsson also teaches formulation of PEA (page 933), oral administration of PEA and associated pharmacokinetic data following oral administration of PEA (page 933, Figure 2). See MPEP § 2144.05.
Applicant’s invention is unpatentable over the teaching of El-Radhi, in view of the teachings of Barkin, Hesselink, Deciga-Campos, Temple and Gabrielsson, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in modifying the known treatments reported by El-Radhi for pediatric fever, of either paracetamol alone or in combination with ibuprofen, to a combination of paracetamol with palmitoylethanolamide (PEA) within the required dose ranges of claim 20, because El-Radhi teaches that the main purpose of administering paracetamol and/or ibuprofen to febrile children is for the analgesic aspect of these agents, and El-Radhi discourages combinations of antipyretics but does not discourage combination treatments that contain only a single antipyretic, while Barkin teaches that analgesic combinations can be synergistic in treating pain across multiple pain centers/etiologies, providing dose reduction and/or minimization of side effects, and because Hesselink teaches that PEA is a known analgesic that is safe to administer to children while Deciga-Campos teaches that paracetamol and PEA work together to provide synergistic, dose-sparing pain relief, and Temple and Gabrielsson teach the determination of safe and efficacious dosing of paracetamol and PEA, respectively.
Thus, the invention was prima facie obvious at the time of filing.
Claim 23 further limits claim 20 with regard to the dosage of paracetamol to specific amount(s) of about 10, 48, 80, 120, 160, 325, 500, or 650 mg, and is met by the rejection above.
Claim 24 further limits claim 20 with regard to the dosage of PEA is about 800 mg, and is met by the rejection above.
Claim 29, 30, 32 and 36 further limit the method of claim 20 with regard to the formulation of the active agents, either for systemic formulation (claim 29), for a Markush group of administration routes that includes subcutaneous (claim 30), “as a solution or as a suppository” (claim 32), and formulated into the same pharmaceutical composition (claim 36). As discussed in the rejection above, Déciga-Campos teaches the administration of the active agents together in solution via subcutaneous injection (systemic).
Claim 33 further limits the method of claim 20 to a desired result of at least one side-effect associated with paracetamol consumption being prevented or treated. Claim 38 further limits claim 33 wherein the side-effect to be prevented or treated is selected from a Markush group that includes “worsening of asthma in asthma patients”. El-Radhi teaches that excessive paracetamol consumption can worsen asthma. A person of ordinary skill in the art would have a reasonable expectation that a combination treatment of paracetamol with PEA would prevent the worsening of asthma because Déciga-Campos teaches that such a combination has a synergy of analgesic effect such that lower dosage(s) will achieve effective pain relief, while El-Radhi teaches that the primary reason for administering paracetamol or another analgesic-antipyretic treatment is to alleviate the symptoms associated with fever, including headache and myalgia. By lowering paracetamol dosages through the synergy of combined paracetamol/PEA administration for the treatment of symptoms associated with fever, a person of ordinary skill in the art would have a reasonable expectation of success that the worsening of asthma from excessive paracetamol consumption would be prevented.
Claim 35 further limits the method of claim 20 with the requirement that the paracetamol and N-acylethanolamine are administered daily. The instant specification does not provide a definition for “daily” administration; therefore the Examiner has applied the Broadest Reasonable Interpretation to this claim, with the term “administered daily” taken to mean that patients receive at least one dose of each active agent per day, with the caveat that the instant specification does state that “daily” administration can allow for occasional interruption of the regimen, providing a day with no dose given (page 11, lines 25-27). Thus once daily (“QID”), twice daily (“BID”), thrice daily (“TID”), or any number of times that is greater than zero/day constitutes daily administration. El-Radhi teaches administration at intervals of 4-6 hours (page 87), which allows for up to 4-6 doses/day. Hesselink teaches administration of PEA twice per day (BID) to pediatric subjects (page 4).
Applicant’s invention is unpatentable over the teaching of El-Radhi in view of the teachings of Barkin, Hesselink, Deciga-Campos, Temple and Gabrielsson because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in modifying the known treatments reported by El-Radhi for pediatric fever, of either paracetamol alone or in combination with ibuprofen, to a combination of paracetamol with palmitoylethanolamide (PEA) and achieving safe and efficacious dosing of both agents, for the following reasons:
The main purpose of administering paracetamol and/or ibuprofen to febrile children is for the analgesic aspect of these agents, per the teaching of El-Radhi, who discourages combinations of antipyretics while not discouraging combination treatments that contain only a single antipyretic;
Analgesic combinations can be synergistic in treating multiple pain centers/etiologies, providing dose reduction and/or minimization of side effects, per the teaching of Barkin;
PEA is a known analgesic that is safe to administer to children, per the teaching of Hesselink;
It was known in the art that paracetamol and PEA work together to provide synergistic, dose-sparing pain relief, per the teaching of Deciga-Campos, who also teaches the administration of the active agents together in solution via subcutaneous injection (i.e., systemic administration);
Safe and efficacious dosages of paracetamol and PEA are result-effective variables, and the determination of safe and efficacious doses of these agents was known in the art, per the teachings of Temple and Gabrielsson, respectively, as well as daily dosing regimens of these agents being additionally known through the teachings of El-Radhi and Hesselink, respectively;
Worsening of asthma is a known side effect of excessive paracetamol administration, per the teaching of El-Radhi, thus the dose-sparing synergistic administration of paracetamol with PEA would be reasonably expected by a person of ordinary skill in the art to prevent this known side effect.
Thus, the invention was prima facie obvious at the time of filing.
Conclusion
THIS ACTION IS MADE FINAL. 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 W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Cited in Applicant’s information disclosure sheet (IDS) dated 12/21/2023.
2 Cited in Applicant’s information disclosure sheet (IDS) dated 12/21/2023.
3 Déciga-Campos, page 229, right column, first full paragraph (emphasis added).