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 .
Claim Rejections 35 USC 103(A)
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.
Claim(s) 1-4, 6-11 and 13 are rejected under 35 U.S.C. 103(A)(1) as being unpatentable over Spaccapelo et al. (European Journal of Pharmacology, Vol. 670, No.2, Sept. 2011, pp. 479-486; See ISR) in view of Clinicaltrials.gov (Phase III Confirmatory Study in Erythropoietic Protoporphyria, https://clinicaltrials.gov/study/NCT01605136, start date, 2012; last updated 12/09/19).
Spaccapelo teaches that melanocortins, specifically MC4R agonists are known to have neuroprotective effects (Abstract). This reference teaches that non-selective [Nle4 ,D-Phe7 ]α-melanocyte-stimulating hormone (NDP-α-MSH/afamelanotide) was tested in a gerbil model of transient global brain ischemia to test its effects on late inflammatory apoptotic machinery and neuronal functionality (p. 480, Col. 1). Spaccapelo induced a transient global cerebral ischemia in gerbils by occluding both common carotid arteries for 10 min (abstract, p. 480, Col. 1). After stroke induction, gerbils were allowed to recover from anesthesia and surgery for 3 days before starting behavioral studies, and observed for the following 11 days (p. 480, Col. 1). In this study, the drugs were dissolved in saline (1 ml/kg) and administered intraperitonially, where control animals received equal volume of saline by the same route (p. 480, Col. 1). Spaccapelo found that in saline-treated stroke animals, an impairment in learning and memory occurred at day 11 after the cerebrovascular accident (i.e. stroke), was associated with hippocampus up-regulation of tumor necrosis factor-α (TNF-α), BAX, activated extracellular signal regulated kinases (ERK1/2), c-jun N-terminal kinases (JNK1/2) and caspase-3, down-regulation of Bcl-2, and resultant neuronal loss, whereas those treated with afamelanotide counteracted the inflammatory and apoptotic responses, as indicated by the changes in TNF-α, BAX, ERK1/2, JNK1/2, caspase-3 and Bcl-2 protein expression (p. 481, spanning Col. 1-2). Over the 11 day treatment period, Spaccapelo found that melanocortin treatment reduced neuronal loss and dose-dependently improved learning and memory (See Fig. 2A and 2B). Spaccapelo also found that NDP-α-MSH effectively reaches the CNS after systemic administration, and that it has a neuroprotective effects for the reduction in BBB permeability that is known to follow strokes (p. 485, Col. 1).
The difference between the prior art and the instant claims is that the prior art does not reduce to practice administering the MC1R/MC4R selective agonist, afamelanotide, to humans for treating a stroke.
However, Spaccapelo specifically teaches that the experimental model of hypoxic–ischemic brain injury used in the afamelanotide study represents human stroke conditions because of the atherosclerotic involvement of the common carotid arteries, respiratory arrest, cardiac arrest, choking and other causes (p. 485, Col. 2).
Furthermore, Clinicaltrials.gov (2012, 2019) teaches that afamelanotide is known to be safe for humans, as it has undergone effective human trials as a treatment for Erythropoietic Protoporphyria since Phase I in 2012, and as of 2019, over 620 subjects have been treated with afamelanotide to date with no serious safety concerns identified (See detailed description). In these human trials, afamelanotide has been formulated as a controlled release depot injection (implant) administered at 0, 60 and 120 days, which slowly releases16mg it into the systemically over a several days (clinicaltrials.gov; detailed description).
As such, it would have been obvious to one of ordinary skill in the art at the time of the invention to have taken the patient class subjects that have undergone a stroke, as taught by Spaccapelo, and administered afamelanotide to human subjects, because it is known to be safe in humans and effective in animal models of stroke that are representative of human ischemic stroke conditions. One would be motivated to do so because Spaccapelo found that the administration of afamelanotide counteracted the inflammatory and apoptotic responses, reduced neuronal loss and dose-dependently improved learning and memory in an experimental model of human stroke conditions. As such, there is a reasonable expectation of success that the method of treating ischemic stroke taught by Spaccapelo can be safely and effectively practiced in human methods of treatment and administration, as taught by Clinicaltrials.gov.
This meets the limitations of claims 1, 3, 4, and 11 by rendering obvious the same hMC4R/hMC1R agonist, afamelanotide, for treating ischemic stroke in humans. Claims 6-8, 10 and 13 are met because both references teach injection routes, and the human trials of Clinicaltrials.gov teach subcutaneous implants of 16mg for controlled release. As to claim 9, this range is not only obvious to optimize, but 16mg would equate to .26mg/kg/day for a 60kg human and .178mg/kg for a 90kg human, which is well within the broad range of .0007mg/kg to 1.5mg/kg for day 1, and renders obvious the range of claim 9. Furthermore, the ranges would be obvious to optimize, based on the variable and routine experimentation. MPEP 2144.05 states: “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. "[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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); 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."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").”
As such, these dosages not only overlap with the claimed ranges, but are also obvious to optimize.
Claim(s) 1-4, 6-12 and 13 are rejected under 35 U.S.C. 103(A)(1) as being unpatentable over Spaccapelo et al. (See ISR) in view of Clinicaltrials.gov, as applied above, and in further view of Holloway et al. (Trends in Pharmacological Sciences, February 2011, Vol. 32, No. 2; See ISR).
The teachings of Spaccapelo and Clinicaltrials.gov have been described supra.
The difference between the prior art and the instant claims is that the prior art does not teach administering tissue plasminogen activator (tPA) prior to afamelanotide after a stroke.
Holloway teaches that intravenous administration of clot-busting tissue plasminogen activator (tPA) remains the only practiced treatment for acute ischemic stroke, but that a restricted 3hr therapeutic window and risk of intracerebral hemorrhage associated with its use indicate an urgent need for more efficient stroke therapies (p. 90). Holloway also teaches that therapeutic manipulation of the melanocortin system has already shown promise in a number of different animal models of stroke, even where treatment has been delayed up to 9 h after the ischemic episode (p. 97, Col. 1). Holloway references the Spaccapelo study, and notes that afamelanotide (NDP-a-MSH) has already showed promise in delayed stroke treatment (p. 97, Col. 1).
As such, it would have been obvious to one of ordinary skill in the art at the time of the invention to have taken the method of treating ischemic stroke taught by Spaccapelo and administered tPA prior to afamelanotide because tPA is known to be effective and is currently in use for treating stroke, but only within 3 hours, whereas afamelanotide has been shown to be effective as late as 9 hours. One would be motivated to administer both in the this regimen for the timing reasons as well as because tPA has shown to be effective in restoring blood flow to the brain after stroke and afamelanotide has been shown to be effective in promoting neuronal regeneration. As such, there is reasonable expectation of success that the treatment of Spaccapelo can be combined with the tPA discussed in Holloway because they are both shown to be effective for treating stroke at different times after the ischemic strokes and by two different mechanisms that both restore CNS function.
As such, claim 12 is rendered obvious over the prior art.
Claim(s) 1-3, 5-11 are rejected under 35 U.S.C. 103 as being unpatentable over Lorrain et al. (WO2008/039863; see ISR) in view of Rosen et al. (International Journal of Impotence Research. Vol. 16, pages135–142, 2004).
Lorrain teaches methods for treating diseases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis via modulation of a melanocortin receptor (MCR) activity, optionally in combination with another neurogenic agent [0002]. Such diseases that are included as those treatable with the MCR regulating agents are neural cells affected by disease or injury, regions containing neural cells associated with disease effects or processes, or regions containing neural cells affected by other events injurious to neural cells, including stroke [0069, 0106, 0120]. Specifically Lorrain teaches treating subject that have suffered a CNS insult, such as a CNS lesion, an ischemic stroke, or other ischemic disorders that degrade neuronal cells [0069, 0404, 0434]. Lorrain further teaches that an MCR agents can be conjugated or complexed with the fatty acid docosahexaenoic acid (DHA), which is readily transported across the blood brain barrier and imported into cells of the CNS [0151].
Lorrain teaches that routes of administration for bremelanotide include subcutaneous injection, and that dosages range from 0.001 ng/kg/day to about 200 mg/kg/day, or .2 to about 2mg/kg/day, but that as understood by those skilled in the art, the exact dosage of an MCR agent used to treat a particular condition will vary in practice due to a wide variety of factors [0147, 0189, 0421, 0420-0422, 0137].
This reference specifically teaches that bremelanotide (PT-141) as a first neurogenesis modulating agent having activity to stimulate or activate the formation of new nerve cells [0017-0019]. Lorrain further teaches administering the MCR agents to humans for neurogenesis, and that human dose equivalents are well known in the art [0131, 0136, 0157]. In support of this, Example 3 shows the effect of bremelanotide on neurogenesis in human neural stem cells (hNSCs). In this example hNSCs were isolated and grown in monolayer culture, plated, treated with varying concentrations of bremelanotide and stained with TUJ-I antibody, using a positive control for neuronal differentiation was used along with basal media without growth factors as a negative control [0441, 0445-0446, Example 3, Fig. 3]. This reference provides a dose response curve of results of human neuronal differentiation where the neuronal positive control is included as a reference and results are presented as a percent of neuronal positive control [Fig. 3]. The results of the study of bremelanotide indicate that it promotes human neuronal cell differentiation, which shows that it can treat ischemic strokes by promoting neuronal cell growth [Fig. 3, 0046].
The difference between the prior art and the instant claims is that the prior art does not specifically reduce to practice administration of bremelanotide to human subjects.
However, Rosen teaches that in two human trials subcutaneously administered doses of bremelanotide ranging from 0.3 to 10 mg were administered to healthy male subjects for erectile dysfunction, and they were statistically significant in efficacy for that purpose, as well as safe and well tolerated in both studies (abstract).
As such, it would have been obvious to one of ordinary skill in the art to have taken the method of treating ischemic stroke taught by Lorrain and administered it to human subjects, because Lorrain teaches that it was effective in human neuronal cell regeneration and Rosen teaches that subcutaneous administration to humans is safe and well tolerated. One would be motivated to administer bremelanotide to humans because of the MCR activity shown in the studies of Lorrain and the impact of stroke on neural generation. As such, there is a reasonable expectation of success that the method of Lorrain can be practiced in vivo in human subjects to effectively tret stroke by neuronal cell differentiation and neurogenesis.
This meets the limitations of claims 1-3 by teaching treatment of a cerebrovascular accidents (ischemic strokes) in humans with the MCR agonist, bremelanotide, which Lorrain also teaches is known to cross the BBB with the aid of a carrier. Claims 5-8 are met because Lorrain teaches subcutaneous injection. Claims 9-10 are met because Lorrain teaches .2 to about 2mg/kg/day, and Rosen teaches that humans were injected with .3 to 10mg safely. Additionally, this dosage would be obvious to optimize, as discussed above. Claim 11 is met because Lorrain teaches that bremelanotide treats ischemic stroke by regenerating human neuronal cells.
Conclusion
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/JEANETTE M LIEB/Primary Examiner, Art Unit 1654