DETAILED ACTION
This action is in response to papers filed on 08/29/2025. Claims 1-15 of F. Della Valle et al., 17/949,754 (09/21/2022) are pending examination on the merits: claims 12-15 remain withdrawn. Claims 1-11 are rejected.
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 .
Priority
This application claims Foreign Priority of application no. IT102021000024464, filed on 09/23/2021 in the Italian Republic.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/29/2025 has been entered.
Election/Restrictions
Applicant provisionally elected with traverse, over the phone, on March 5, 2024, Group I: claims 1-11, drawn to a method of treating autism spectrum disorder (ASDs), as required under 35 U.S.C. 121. Groups II (claims 12-13) and III (claims 14-15), drawn to a method of treating depressive syndromes, and to a composition/pharmaceutical or veterinary formulation respectively, are withdrawn from consideration.
In a response filed on 06/24/2024, Applicant confirmed the election of Group I with traverse (Applicant’s Remarks, p. 5). The Election/Restriction is maintained as FINAL.
Claim Interpretation
Claims 2-6 is drawn to a method of claim 1, wherein:
“… having a particle size distribution, defined as percentage by volume
and measured by the laser light scattering method, represented by a
distribution curve …”
The specification does not identify and/or define the exact parameters of “the laser light scattering method”, but rather provides exemplary ways in which particle size can be obtained (e.g., pp. 16-17, such as a Low Angle Laser Light Scattering technique, that may be performed with a Malvern Mastersizer 3000 instrument). The phrase is considered to be ambiguous, as it is unclear whether they are simply informational or part of the limitation of the claim. However, the phrase appears to define “particle size distribution”, as a standard measure of percentage by volume, and how it may be measured (i.e., using laser light scattering method).
Therefore, the phrase: “… having a particle size distribution, defined as percentage by volume and measured by the laser light scattering method, represented by a distribution curve …”, present in claims 2-6, is interpreted to be informational, and not further limiting of the claims. The Broadest Reasonable Interpretation of claims 2-6, therefore, as it relates to the particle size distribution of palmitoylethanolamide, is interpreted as the mode between the specified ranges in microns respectively, as recited in each claim.
Claim Rejections - 35 USC § 103
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.
Claims 1, 7, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Bertolino et al., (2017); CNS Neurosci Ther. 2017 Jan;23(1):87-98, in view of Pangrazzi et al., (2020), Antioxidants (Basel), 2020 Nov 26;9(12):1186, and as evidenced by Antonucci et al., Case Reports in Psychiatry (2015) (pp. 1-6) (“Antonucci”) and Petrosino et al. (2016); Br J Pharmacol Sept 29; 174(11):1349-1365.
Regarding claim 1, Bertolino teaches a method of treating autism spectrum disorders (ASDs), wherein palmitoyethanolamide (PEA) is administered to a patient in association with Luteolin, a flavonoid, wherein said administration is combined (see, for e.g., Abstract).
More specifically, Bertolino discloses that the association of the fatty acid amide palmitoylethanolamide (PEA), with the flavonoid luteolin displays neuroprotective and anti-inflammatory actions in different models of central nervous system pathologies. Bertolino also discloses that “… N-Palmitoylethanolamine (PEA) behaves as a lipid signaling molecule with anti-inflammatory activity in preclinical models of acute and inflammatory pain and central nervous system injury and is efficacious for pain relief in man…”, while Luteolin “… a flavonoid belonging to the flavone family, possesses neuroprotective actions…”, antioxidant, anticancer, memory-improving, and anxiolytic activities (p. 88). That is, to one of ordinary skill, Luteolin is known to protect neurons from oxidative stress and inflammation.
Bertolino, however, does not teach the method according to claim 1, “… wherein palmitoylethanolamide is administered to a patient in association with docosahexaenoic acid (DHA)…”.
Pangrazzi in Table 1 (p. 10), summarizes the effects of natural antioxidants on autism spectrum disorder (ASD) in animal models and in humans with ASD. Pangrazzi discloses different formulations, including the above Palmitoylethanolamide and luteolin, along with DHA and eicosapentaenoic acid (EPA), that have a therapeutic effect on ASD, in humans with ASD. Dose, duration of the treatment, species, molecular effects, and behavioral improvements are also reported in the table.
To one of ordinary skill in the art, DHA is particularly known to have neuroprotective properties that are essential for brain health, including the protection against neurodegenerative diseases. On p. 8, Pangrazzi further discloses that “… DHA constitutes 90% of the whole amount of omega-3 in the human brain and 10–20% of total lipids. A link between abnormal fatty acid metabolism and the pathophysiology of ASD has been reported…”.
It would have therefore been prima facie obvious, for one of ordinary skill in the art, to modify the teachings of Bertolino, in view of Pangrazzi to arrive at the claimed invention – “A method for the treatment of autism spectrum disorders (ASDs), wherein palmitoylethanolamide is administered to a patient in association with docosahexaenoic acid (DHA), wherein said administration is separate, combined, or simultaneous”.
One of ordinary skill in the art would have been motivated to do so, with reasonable expectation of success, because Bertolino teaches a method of treating ASD, using co-ultramicronized PEA with luteolin (Abstract). Bertolino teaches PEA as a lipid signaling molecule with anti-inflammatory activity in inflammatory pain and central nervous system injury, and Luteolin as a flavonoid that possesses neuroprotective actions (p. 88). As evidenced by Antonucci et al., Case Rep Psychiatry 2015 (pp. 1-6), PEA alone is shows beneficial effects on expressive language, cognition, and behaviors in Autism (Abstrac; and, p. 4, Table 1):
PNG
media_image1.png
894
819
media_image1.png
Greyscale
Pangrazzi in Table 1 not only teaches the same PEA and Luteolin combination as Bertolino, but also provides alternative formulations such as DHA and EPA. These formulations, as disclosed by both Bertolino and Pangrazzi are known to have strong effects on ASD, both on the molecular and behavioral levels. Moreover, Pangrazzi teaches DHA, similar to luteolin, as one that also has neuroprotective properties/activities, and is essential for brain health, including protection against neurodegenerative diseases. DHA, as disclosed by Pangrazzi, constitutes 90% of the whole amount of omega-3 in the human brain.
PEA, DHA and EPA are fatty acids/fatty acid amide with neuroprotective properties and/or activities, and are shown to be therapeutically effective in improving the symptoms ASD as disclosed by Bertolino and Pangrazzi. Luteolin, a flavonoid, also shares said neuroprotective properties and is also effective in improving the symptoms of ASD as disclosed above. It is therefore within the skill of one of ordinary skill in the art, to modify the disclosed formulations and arrive at the claimed combination, by substituting luteolin with DHA, and arrive at the claimed method of treating ASD, “wherein palmitoylethanolamide is administered to a patient in association with docosahexaenoic acid (DHA)…”. Both luteolin and DHA are anti-inflammatory, antioxidant, neuroprotective agents that have been implicated in the treatment of ASD, as disclosed above by Bertolino and Pangrazzi, by virtue of their neuroprotective properties. Combining PEA with DHA, similarly to the above counterparts, is therefore expected to have neuroprotective effects in the treatment of ASD as required by the claim. Claim 1 is therefore obvious over Bertolino and Pangrazzi.
Regarding: “and wherein, when said administration is combined, said palmitoylethanolamide and said DHA are present as a mixture”.
As disclosed above, in both instances Bertolino (Abstract: “we investigated the effect of association of ultramicronized PEA with luteolin, co-ultramicronized PEA-LUT (co-ultra PEA-LUT) in a murine model of autistic behaviors, while in the second, the effect of co-ultraPEA-LUT in a patient affected by ASD was examined”; Bertolino also teaches on p. 89: “we undertook a therapy with the antiinflammatory and mast cell modulating agent co-ultraPEA-LUT, at a dose of 700mg+70mg b.i.d. (Glialia®) microgranules, Epitech Group SpA, Italy) for 1 year.”. As disclosed, the microgranules contain 700 mg of PEA + 70 mg Luteolin in a co-ultramicronized form. The ratio disclosed of PEA to Luteolin is 10:1. Pangrazzi also (p. 10, Table 1), teaches combinations of the above disclosed flavonoids in the treatment of autism (i.e., Pangrazzi Table 1 teaches, for example, Palmitoylethanolamide and luteolin at 700 mg orally and at 1 mg/kg orally, and DHA and EPA between 700 mg – 1.5 g orally).
As evidenced by Petrosino et al., co-ultraPEALut consists of a mixture of PEA and antioxidant flavonoid Leutolin (see section PEA and neurological disorders-neurodegenerative diseases 2nd paragraphs). Petrosino et al. also disclose that administration of this composite, which consists of a mixture of an anti-inflammatory mediate (i.e., PEA) and an antioxidant compound (i.e., luteolin) produces complimentary and synergistic effects by active simultaneously on two phenomenon-inflammation and formation of reactive oxygen species (see last paragraph of the section PEA and neurological disorders-Neurovegetative diseases). Thus, Petrosino et al. provides evidence that the co-ultraPEA-LUT is a mixture.
It would have therefore been prima facie obvious, to one of ordinary skill in the art, before the effective filing date of the claimed invention, to substitute luteolin (i.e., in the combination of PEA-Luteolin) as disclosed by Bertolino, for DHA as disclosed by Pangrazzi, and arrive at the claimed proviso of “and wherein, when said administration is combined, said palmitoylethanolamide and said DHA are present as a mixture”. One of ordinary skill in the art would have been motivated to substitute luteolin for DHA, as DHA, similar to Luteolin, is particularly known to have neuroprotective properties that are essential for brain health, including the protection against neurodegenerative diseases (Pangrazzi, p. 8: “… DHA constitutes 90% of the whole amount of omega-3 in the human brain and 10–20% of total lipids. A link between abnormal fatty acid metabolism and the pathophysiology of ASD has been reported…”). This combination provides another alternative to treating ASD, based on the finite combinations disclosed by the prior art. Furthermore, Pangrazzi demonstrated combinations of flavonoids in Table 1, describing the effects of these natural antioxidants on autism spectrum disorder (ASD) animal models and humans with ASD, along with reports of dose, duration of the treatment, species, molecular effects, and behavioral improvements. It is within the technical grasp of one of ordinary skill in the art, to optimize the combinations, and arrive at the claimed invention.
Moreover, the level of skill and knowledge in the art is replete with regards to the use of PEA, DHA, EPA, Luteolin, among other flavonoids for treating autism, either alone or in combination. MPEP 2141.03 states (in part), “A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR International Co. v.Teleflex Inc., 127 S.Ct. 1727, 167 LEd2d 705, 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At 1396, 82 USPQ2d at 1396. The “hypothetical person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988).
Modifying Bertolino, in view of Pangrazzi, to arrive at the claimed invention, includes optimizing the ratio amount of PEA to DHA, in order to arrive at the claimed invention successfully based on desired effects. Bertolino discloses a co-ultramicronized form that of PEA to Luteolin as 10:1, which encompasses the high-end of the disclosed range of the modified invention of PEA to DHA. It is within the skill of an artisan to adjust the amount of a component in a composition to obtain the desired ratio, and routinely arrive at the claimed invention. See In re Aller, 220 F.2d 454,456, 105 USPQ 233,235 (CCPA 1955) which states, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See MPEP § 2144.05, "II. Optimization of Ranges".
Regarding claim 7, the method according to claim 1, wherein PEA and DHA are administered in a weight ratio between 1:7 and 7:1, while Bertolino in view of Pangrazzi, as applied to claim 1, does not explicitly teach the weight ratio between PEA and DHA, this can be determined experimentally based on the desired therapeutic effect.
Bertolino teaches on p. 89: “we undertook a therapy with the antiinflammatory and mast cell modulating agent co-ultraPEA-LUT, at a dose of 700 mg+70 mg b.i.d. (Glialia®
microgranules, Epitech Group SpA, Italy) for 1 year.”. As disclosed, the microgranules contain 700 mg of PEA + 70 mg Luteolin in a co-ultramicronized form. The ratio disclosed of PEA to Luteolin is 10:1.
However, as disclosed above and applied to claim 1, the prima facie case of modifying Bertolino, in view of Pangrazzi, to arrive at the claimed invention, includes optimizing the ratio amount of PEA to DHA, in order to arrive at the claimed invention successfully based on desired effects. Bertolino discloses a co-ultramicronized form that of PEA to Luteolin as 10:1, which encompasses the high-end of the disclosed range of the modified invention of PEA to DHA. Moreover, it is within the skill of an artisan to adjust the amount of a component in a composition to obtain the desired ratio, and routinely arrive at the claimed invention. See In re Aller, 220 F.2d 454,456, 105 USPQ 233,235 (CCPA 1955) which states, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See MPEP § 2144.05, "II. Optimization of Ranges". Claim 7, as is claim 1, is also obvious over Bertolino, in view of Pangrazzi.
Regarding claim 10, “The method according to claim 1, wherein palmitoylethanolamide and DHA are contained in pharmaceutical or veterinary formulations and are formulated in dosage forms for oral, buccal, parenteral, rectal, or transdermal administration”, Bertolino in view of Pangrazzi discloses teaches the limitation.
As applied above to claim 1, the teaching of Bertolino in view of Pangrazzi is disclosed.
Bertolino on p. 88, administered the disclosed formulation orally, and Pangrazzi in Table 1, shows various ways in which the formulations/molecules can be administered including orally, IV: intravenously; IP: intraperitoneally; or by VPA: valproic acid (see, for e.g., p. 10, Table 1).
It would have been obvious to one of ordinary skill in the art to claim these routes of administration in a method of treating autism, considering that, not only are these typical routes of administration in the art, but it has been demonstrated by both Bertolino and Pangrazzi, that similar formulations, used in the treatment of autism, have been administered orally, and intravenously, for example. One would have been motivated to administer the claimed formulation, using these standard routes of administration, with reasonable expectation of success. Claim 10, as is claim 1, is also obvious over Bertolino, in view of Pangrazzi.
Claims 2-3 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Bertolino et al., (2017) in view of Pangrazzi et al., (2020), as evidenced by Antonucci et al. (2015) and Petrosino et al. (2016) as applied to claims 1, 7 and 10 above, and in further view of Comelli et al., (1999), EP 1207 870 B1.
Regarding claims 2-3, the modification of Bertolino in view of Pangrazzi as applied to claim 1 above, teaches the method according to claim 1, wherein palmitoylethanolamide is administered to a patient in association with docosahexaenoic acid (DHA), wherein said administration is combined.
However, Bertolino in view of Pangrazzi as applied to claim 1, does not disclose PEA in:
“… a non-micronized form, having a particle size distribution, …, above 10 microns, preferably above 20 microns”, as applied to claim 2, and
“… a micronized form, having a particle size distribution, …, between 6 microns and 10 microns”, as applied to claim 3.
Comelli teaches PEA in a “non-micronized…having a particle size distribution above 10 microns, preferably above 20 microns”, and “… a micronized form, having a particle size distribution, …, between 6 microns and 10 microns”. In the prepared composition, Comelli teaches a trace percentage of PEA particles with a size distribution of greater than 14 microns (non-micronized), approximately 96% of PEA particles with a particle size distribution of less than 10 microns and 80% of PEA particles with a particle size distribution of less than 6 microns (see, for e.g., p. 4, [0026]).
Comelli also teaches the use of n-palmitoylethanolamide, in a micronized and/or co-micronized form, for the preparation of pharmaceutical compositions for veterinary use (see, for e.g., p. 2, [0014]). Comelli also discloses that the micronization of PEA and its co-micronization with excipients were performed with compressed-air turbine micronizing apparatus, and the product obtained was subjected to analysis of the particles with Mastersizer (see, for e.g., p. 4, [0026]). The final fineness of the PEA particles produced is summarized below (see, for e.g., p. 4, [0026]):
PNG
media_image2.png
96
184
media_image2.png
Greyscale
It would have been prima facie obvious to one of ordinary skill in the art to modify the teachings of Bertolino in view of Pangrazzi, as applied to claim 1: “a method of treating autism spectrum disorder (ASD), wherein palmitoylethanolamide (PEA) is administered to a patient in association with docosahexaenoic acid (DHA)”, in view of Comelli, to arrive at the claimed invention. That is, wherein palmitoylethanolamide is in “… a non-micronized form, having a particle size distribution … above 10 microns, preferably above 20 microns”, and in “… a micronized form, having a particle size distribution, … between 6 microns and 10 microns”. In its original, “non-micronized form”, PEA is certainly expected to have a particle size distribution mode that is greater than the particle size distribution mode in its micronized form. Micronizing PEA, a lipophilic molecule, as disclosed by Comelli, the extreme fineness of the particles can be translated into improved absorption of the drug (see, for e.g., p. 4, ll. 15-20). Therefore, one would have been motivated to modify the teachings of Bertolino in view of Pangrazzi, as applied to claim 1 above, in further view of Comelli, to arrive at the claimed invention with reasonable expectation of success such as improved therapeutic effects.
Regarding claim 9, “the method according to claim 1, wherein the daily dose of PEA for administration to a subject, ranges from 10 mg to 1500 mg …” is disclosed by Bertolino in view of Pangrazzi, as applied to claim 1 in view of Comelli.
As applied above to claim 1, Bertolino in view of Pangrazzi teachings are disclosed.
Bertolino in view of Pangrazzi, as applied to claim 1, however does not explicitly teach “the method according to claim 1, wherein the daily dose of PEA for administration to a subject, ranges from 10 mg to 1500 mg …”.
Comelli teaches in Example 1, “the daily dose of PEA for administration to a subject, ranges from 10 mg to 1500 mg …” (see, for e.g., p. 4, [0027]):
PNG
media_image3.png
489
1277
media_image3.png
Greyscale
In Example 1, micronized PEA was present in an amount of 120 mg. Comelli also discloses that the composition for administration to cats contains from 20 mg to 4 g of PEA per 100 g of composition (see, for e.g., p. 4, [0028]).
As it relates to claim 9, it would have been prima facie obvious to one of ordinary skill in the art to modify the method disclosed by Bertolino in view of Pangrazzi, as applied to claim 1s, in view of Comelli, to arrive at the claimed invention.
The claimed invention:
“The method according to claim 1, wherein the daily dose of PEA for administration to a subject range from 10 mg to 1500 mg …”
Bertolino in view of Pangrazzi, as applied to claim 1 discloses a method of treating autism spectrum disorder (ASD) by administering PEA to a patient in association with docosahexaenoic acid (DHA). Comelli discloses veterinary compositions, whereby micronized PEA was present in an amount of 120 mg. Comelli also discloses that the composition for administration to cats contains from 20 mg to 4 g of PEA per 100 g of composition (see, for e.g., p. 4, [0028]). Therefore, one of ordinary skill in the art would have been motivated to modify the method disclosed by Bertolino in view of Pangrazzi, as applied to claim 1s, in view of Comelli, as the dosage disclosed by Comelli provides a framework from which the dosage of PEA can be optimized, with reasonable expectation of success. Furthermore, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. Therefore, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."). See, MPEP § 2144.05 (II), “Routine Optimization”.
Claims 4-6 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Bertolino et al., (2017) in view of Pangrazzi et al., (2020) as evidenced by Antonucci et al. (2015) and Petrosino et al. (2016) as applied to claims 1, 7 and 10 above, and further in view of Della Valle et al., (2014), 8,663,701 B2.
Regarding claim 4, the limitation “…the method according to claim 1, wherein palmitoylethanolamide is in … an ultra-micronized form, having a particle size distribution, …, having the mode below 6 microns and above 0.5 microns” is disclosed by Bertolino in view of Pangrazzi as applied to claim 1 above, and in further view of Della Valle.
As applied above to claim 1, Bertolino in view of Pangrazzi teachings are disclosed.
Bertolino in view of Pangrazzi, as applied to claim 1 above, however, does not explicitly teach palmitoylethanolamide (PEA) in “… an ultra-micronized form, having a particle size distribution … having the mode below 6 microns and above 0.5 microns”
Della Valle teaches the particle size profile of ultra-micronized PEA compared to the particle size profile obtained through a simple micronization:
PNG
media_image4.png
271
531
media_image4.png
Greyscale
As disclosed by Della Valle, the ultra-micronized form of PEA has a particle size distribution with a mode below 6 microns and above 0.5 microns as shown in Table 1 (see, for e.g., Table 1, col. 5, ll. 5-20). Furthermore, Della Valle also discloses that the particle size was measured, using a laser particle size analyzer (Malvern Mastersizer) with LALLS (Low Angle Laser Light Scattering) technique using the Fraunhofer theory of computation (see, for e.g., col. 5, ll. 20-24).
It would have been prima facie obvious to one of ordinary skill in the art to modify the teachings of Bertolino in view of Pangrazzi, as applied to claim 1 above, “a method of treating autism spectrum disorder (ASD), wherein palmitoylethanolamide (PEA) is administered to a patient in association with docosahexaenoic acid (DHA)”, in view of Della Valle, “wherein palmitoylethanolamide is in … an ultra-micronized form, having a particle size distribution … having the mode below 6 microns and above 0.5 microns”, to arrive at the claimed invention. It is known in the art that neuroinflammation is involved in the etiology of ASD, for example, and as disclosed by Della Valle, the pharmacological effect on neuroinflammatory processes “is mediated by the ability of ultra-micronized PEA to significantly increase the release of the endocannabinoid 2-arachidonoylglycerol (2-AG)” (see, for e.g., col. 16, ll. 30-35), as well as increase the overall absorption of PEA itself. That is, the ultra-micronized “particle size profile of the PEA, and such different crystalline structure characterized by a higher energy content, corresponds to an exponentially increased pharmacological activity compared to the micronized PEA” (see, for e.g., col. 4, ll. 30-35). Therefore, one would have been motivated to modify the teachings of Bertolino in view of Pangrazzi, as applied to claim 1, to treat ASD, wherein palmitoylethanolamide (PEA) is administered to a patient in association with docosahexaenoic acid (DHA), in view of Della Valle, “having the mode below 6 microns and above 0.5 microns”, with reasonable expectation of success, such as improved therapeutic effects.
Regarding claim 5, the limitation “… the method according to claim 4, wherein palmitoylethanolamide has a particle size distribution, wherein at least 95% by volume, preferably at least 99% by volume, of particles has a particle size less than 6 microns”, is disclosed by Bertolino in view of Pangrazzi, and in further view of Della Valle.
As applied above to claim 4 above, the teachings of Bertolino in view of Pangrazzi, and in further view of Della Valle are disclosed.
Della Valle further teaches, “wherein palmitoylethanolamide has a particle size distribution, …., wherein at least 95% by volume, preferably at least 99% by volume, of particles has a particle size less than 6 microns” (see, for e.g., Table 1, col. 5, ll. 5-20) In Table 1, Della Valle discloses the particle size profile of ultra-micronized PEA, in Product B of Table 1 shown above, whereby 99.9% of the ultra-micronized PEA has a particle size of less than 6 microns (see, for e.g., Table 1, col. 5, ll. 5-20).
Regarding claim 6, “the method according to claim 4, wherein palmitoylethanolamide has a particle size distribution, …., having a mode between 2 and 4 microns and having 100% by volume of particles less than 10 microns and at least 60% by volume of particles less than 3 microns”, is disclosed by Bertolino in view of Pangrazzi, and in further view of Della Valle.
As applied above to claim 4, the teachings of Bertolino in view of Pangrazzi, and in further view of Della Valle are disclosed.
Della Valle further teaches, “wherein palmitoylethanolamide has a particle size distribution, …., having a mode between 2 and 4 microns and having 100% by volume of particles less than 10 microns and at least 60% by volume of particles less than 3 microns” (see, for e.g., Table 1, col. 5, ll. 5-20). More specifically,Della Valle teaches the particle size profile of ultra-micronized PEA, in Product B of Table 1 (see, for e.g., Table 1, col. 5, ll. 5-20) shown above, whereby 99.9% of the ultra-micronized PEA has a particle size of less than 6 microns and 59.6% of particles having a particle size of less than 2 microns, for example. Also disclosed by Della Valle in Table 1 is, 100% by volume of PEA particles in product B is less than 10 microns, and at least 60% by volume of particles is less than 3 microns (see, for e.g., Table 1, that is, 59.6% of PEA particles is less than 2 microns, while 99.9% is <6 microns).
As applied to claims 5-6, it would have been prima facie obvious to one of ordinary skill in the art to modify the combined teachings of Bertolino in view of Pangrazzi, as applied to claim 4, and in further view of Della Valle, to arrive at the claimed invention. Dalle Valle discloses, wherein palmitoylethanolamide is in an ultra-micronized form, whereby 99.9% of the ultra-micronized PEA has a particle size of less than 6 microns, for example, and 100% of the ultra-micronized PEA has a particle size of less than 10 microns. It is known in the art that neuroinflammation is involved in the etiology of ASD, for example, and as disclosed by Della Valle, the pharmacological effect on neuroinflammatory processes “is mediated by the ability of ultra-micronized PEA to significantly increase the release of the endocannabinoid 2-arachidonoylglycerol (2-AG)” (see, for e.g., col. 16, ll. 30-35), as well as increase the overall absorption of PEA itself. Therefore, one would have been motivated to modify the teachings of Bertolino in view of Pangrazzi, as applied to claim 4, to treat ASD, wherein palmitoylethanolamide (PEA) is administered to a patient in association with docosahexaenoic acid (DHA), in view of Della Valle, with reasonable expectation of success to arrive at the claimed invention.
Regarding claim 8, the teachings of Bertolino in view of Pangrazzi, and in further view of Della Valle, as applied to claim 4 above, is disclosed.
However, the teachings of Bertolino in view of Pangrazzi, and in further view of Della Valle, as applied to claim 4 above, does not teach “wherein the PEA/DHA weight ratio is between 1:7 and 1:1, preferably between 1:5 and 1:2”; but again, this can be determined experimentally based on the desired therapeutic effect.
As applied to claim 8, it would have been prima facie obvious for one of ordinary skill in the art, to modify the teachings of Bertolino in view of Pangrazzi, as applied to claim 4, and in further view of Della Valle to arrive at the claimed invention –
[claim 4] “Wherein, palmitoylethanolamide is in an ultra-micronized form having a particle size distribution … having the mode below 6 microns and above 0.5 microns”
[claim 8] “the method according to claim 4, wherein the PEA/DHA weight ratio is between 1:7 and 1:1, preferably between 1:5 and 1:2”.
One would have been motivated to do so, with reasonable expectation of success, because the method of treating autism spectrum disorder (ASD) by administering PEA to a patient in association with docosahexaenoic acid (DHA) has been disclosed by Bertolino in view of Pangrazzi. It is known in the art that micronized and ultra-micronized PEA increases the absorption of PEA particles, resulting in improved therapeutic effects, as disclosed by Della Valle. The ratio of PEA to DHA is considered routine and can be determined experimentally, and routinely optimized, in order to achieve the desired results. Furthermore, generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. Therefore, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."). See, MPEP § 2144.05 (II), “Routine Optimization”.
Claims 1 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Bertolino et al. (2017) in view of Pangrazzi et al. as evidenced by Antonucci et al. (2015) and Petrosino et al. (2016) as applied to claims 1, 7 and 10, and further in view of Peritore et al., (2019), Nutrients (2019), 11, 2175.
Regarding claim 11, and as applied above to claim 1, Bertolino in view of Pangrazzi, teach a method for the treatment of autism spectrum disorders (ASDs), wherein palmitoylethanolamide is administered to a patient in association with docosahexaenoic acid (DHA), wherein said administration is separate, combined, or simultaneous.
However, Bertolino in view of Pangrazzi, as applied to claim 1 does not teach, “the method according to claim 1, wherein palmitoylethanolamide and DHA are contained in dietary compositions, food supplements, or foods for special medical purposes (FSMPs)”.
Peritore teaches that palmitoylethanolamide (PEA) is both a naturally occurring lipid ingredient contained in foods/dietary supplements and an endogenous lipid mediator belonging to the class of fatty acid ethanolamides (see, for e.g., p. 2). Moreover, Peritore also discloses that the use of the dietary supplement that is based on omega-3s leads to an increase in the concentration of DHA in tissues, cells, and plasma (see, for e.g., p. 2, N-Acylethanolamines and Diets).
It would have therefore been prima facie obvious for one of ordinary skill in the art to modify the teachings of Bertolino in view of Pangrazzi, as applied to claim 1, in view of Peritore, to arrive at the claimed invention. Bertolino in view of Pangrazzi, as applied to claim 1, teach a method of treating autism spectrum disorder (ASD), wherein palmitoylethanolamide is administered to a patient in association with docosahexaenoic acid (DHA) according to claim 1. Peritore teaches that PEA is a naturally occurring lipid ingredient contained in foods/dietary supplements. Moreover, PEA, as disclosed by Peritore is particularly known for its ability to counteract the inflammatory cascade (see, for e.g., Abstract). Peritore also discloses that the use of the dietary supplement that is, for example, based on omega-3s leads to an increase in the concentration of DHA (known in the art to be a critical component of brain cell membranes) in tissues, cells, and plasma. One would be motivated to do so, with reasonable expectation of success because neuroinflammation is known to be involved in the etiology of ASD; and as disclosed by Peritore, the anti-inflammatory action of PEA combinate with an antioxidant (such as DHA) could potentiate its pharmacological effects. Hence, modifying, “the method according to claim 1, wherein palmitoylethanolamide and DHA are contained in dietary compositions, food supplements, or foods for special medical purposes (FSMPs)” is reasonable and obvious over the prior art.
Applicant’s Arguments
Applicant’s core argument is that the cited prior art references (Bertolino, Pangrazzi, Antonucci, Petrosino, Comelli, Della Valle, and Peritore) do not render the claim obvious under 35 U.S.C. § 103, because they disclose different substances, mechanisms, and combination than what is being claimed. Applicant’s overall position is that the Examiner’s rejection relies on mischaracterizing PEA and DHA (calling them antioxidants). Applicant argues that both PEA and DHA are anti-inflammatory, and not antioxidants, and as such, the proposed combination of the prior arts would require a change in the principle of operation, which Applicant states cannot form a prima facie case of obviousness.
Applicant also argued the individual references, and the arguments are summarized as follows:
Bertolino
Bertolino teaches the efficacy of co-ultra-PEALUT in autism.
Applicant stresses that co-ulta-PEALUT is a composite derived via co-micronization and is different from PEA alone.
Therefore, what Bertolino teaches about co-ulta-PEALUT does not apply to PEA by itself.
Pangrazzi
Pangrazzi describes autism as involving oxidative stress, dyregulated vitamin pathways, and inflammation.
Mentions nutraceuticals (including astaxanthin) with potential benefits.
EPA/DHA are mentioned, without clear evidence of efficacy for core autism symptoms.
Literature cited (e.g., Voigt studies) show no significant improvement in autism symptoms with DHA.
Applicant emphasizes that DHA is anti-inflammatory, not an antioxidant.
Applicant argues Pangrazzi does not establish DHA’s role in antioxidant mechanisms; therefore, combining DHA with PEA (as claimed) is not taught or suggested by Pangrazzi.
Antonucci
Provides only case reports of PEA alone improving autism symptoms.
Does not suggest combining PEA and DHA or antioxidants.
Peritore
Applicant argues that Peritore was cited to satisfy the deficiencies of Bertolino in view of Pangrazzi.
Applicant argues that Peritore teaches anti-inflammatory effects of PEA and that PEA lacks antioxidant capacities.
Applicant argues that Peritore teaches nothing about combining PEA with DHA and does not remedy gaps in Bertolino or Pangrazzi.
Applicant requests withdrawal of the §103 rejections on an alleged premise that the prior arts fail to disclose or suggest the claimed combination of PEA (anti-inflammatory) with DHA (another anti-inflammatory).
Examiner’s Response
Applicant’s response has been carefully considered, but is not found to be persuasive.
One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Where an applicant’s reply establishes that each of the applied references fails to teach a limitation and addresses the combined teachings and/or suggestions of the applied prior art, the reply as a whole does not attack the references individually as the phrase is used in Keller and reliance on Keller would not be appropriate. This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012). MPEP § 2145. The combination of references continues to render the claimed subject matter obvious for the following reasons:
Bertolino et al., (2017)
Applicant argues that Bertolino teaches only co-ultra-PEALUT, a composite formulation of PEA and luteolin, and not PEA itself. This argument is not persuasive because Bertolino nevertheless teaches the clinical efficacy of PEA-containing formulations in autism. A person of ordinary skill in the art (POSITA) would reasonably understand that PEA contributes to the therapeutic effect, and would be motivated to explore other known bioactive co-agents beyond luteolin. Furthermore, substitution of luteolin with another compound known in the art to modulate oxidative stress and inflammation (e.g., DHA, per Pangrazzi) would have been an obvious design choice, and not an inventive step. Both DHA (docosahexaenoic acid) and PEA (palmitoylethanolamide) are well-documented in the scientific literature as having both anti-inflammatory (c.f., Pangrazzi on page 1, teaches that DHA aids in the reducing the synthesis of pro-inflammatory mediators), and antioxidant properties (c.f., Bertolino at Table 1 summarizes studies describing the effects of natural antioxidants, singularly or in a formulation, on ASD which includes DHA and PEA).
Pangrazzi et al. (2020)
Applicant argues that Pangrazzi merely lists nutraceuticals and that DHA’s efficacy in autism is not established. This is also not found to be persuasive because Pangrazzi explicitly discloses that autism is characterized by oxidative stress and inflammation, and highlights nutraceuticals such as DHA and astaxanthin as relevant agents with both anti-inflammatory and antioxidant properties. Even if clinical outcomes with DHA are debated, obviousness does not require absolute predictability, but a reasonable expectation of success. See MPEP 2143.02. A POSITA would have been motivated to combine DHA with PEA to target both inflammatory and oxidative pathways implicated in autism spectrum disorder (ASD), consistent with Pangrazzi’s teachings.
Antonucci et al. (2015) and Petrosino et al. (2016)
Applicant argues these references only show reports of PEA alone; however, this is not found to be persuasive either. Antonucci and Petrosino confirm that PEA is effective in ameliorating autistic symptoms through anti-inflammatory mechanisms. These findings reinforce PEA’s role as a rational baseline therapy, which a POSITA would naturally consider enhancing via combination with other agents targeting oxidative stress (e.g., DHA from Pangrazzi).
Peritore et al. (2019)
Applicant argues Peritore confirms that PEA lacks antioxidant capacity and teaches nothing about combining PEA with DHA. This actually supports the Examiner’s rationale: PEA alone is anti-inflammatory, but not antioxidant, while DHA is both anti-inflammatory and antioxidant. A POSITA, motivated by Pangrazzi’s recognition of oxidative stress in autism, would have been led to combine PEA (anti-inflammatory) with DHA (anti-inflammatory + antioxidant) to address complementary pathological mechanisms. The fact that Peritore emphasizes PEA’s lack of antioxidant properties creates the exact motivation to supplement it with an antioxidant like DHA.
Finally, Applicant’s arguments around the principle of operation (i.e., combining PEA and DHA requires a change in the principle of operation) is not found to be persuasive. Both PEA and DHA share overlapping anti-inflammatory and are documented in the art as relevant to ASD-related pathology. Combining them does not change the principle of operation, but rather represents a predictable use of known agents with similar and complementary functions. Their therapeutic action is clearly not confined to a single mode of activity, and neither compound is limited to a singular biological mechanism.
Accordingly, the mere use of DHA and PEA together as anti-inflammatory agents does not distinguish the claimed method from the prior art teachings of the same or similar combinations used for their combined antioxidant and anti-inflammatory effects. The characterization of these compounds solely by one of their functional properties is an oversimplification that does not support novelty in the instant invention.
For these reasons, it is clear that the cited references collectively establish motivation to combine (i.e., autism involves inflammation and oxidative stress per Pangrazzi; PEA improves ASD symptoms per Antonoccui, Petrosino, and Bertolino; DHA provides both anti-inflammatory and antioxidant effects as per Pangrazzi and Peritore). As it relates to reasonable expectation of success and predictability, each agent is individually disclosed as beneficial in ASD-related pathology, and their mechanisms are complementary. Combining known agents for their additive benefits falls squarely within the type of optimization that is considered obvious under KSR. Accordingly, a prima facie case of obviousness remains established, and Applicant’s arguments do not overcome the rejection.
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 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, and 12-19 of copending Application No. 18303789 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-11 of the instant application is directed towards treating a neurobehavioral disorder, more specifically autism. The method of treatment, disclosed by the instant application, includes administering PEA and DHA, wherein PEA is preferably in a micronized/ultra-micronized form, with particular size distribution within certain micron ranges. Similarly, claims 1-6, and 12-19 of the co-pending application is directed towards treating neurobehavioral disorders, including autism (see, for e.g., claims 1 and 17 of co-pending application), by administering the same components, PEA and DHA (see, for e.g., claim 12 of co-pending application); whereby, PEA is in a micronized/ultra-micronized form (see, for e.g., claim 18 of co-pending application), and whereby the formulation is contained in dietary compositions, food supplements, or foods for special medical purposes (FSMPs) (see, for e.g., claim 19 of co-pending application).
It would have therefore been prima facie obvious for one skilled in the art to claim the instant method of treating autism, using DHA and PEA, in view of the co-pending claims, drawn to a