DETAILE/D ACTION
This action is in response to papers filed on 12/22/2025. Claims 75, and 85-103 of R. Mead et al., 17286797 (04/19/2021) are pending examination on the merits: claim 75 is amended, claims 76-84 have been previously canceled, claims 92-103 have been newly added, and claims 88-90 and 95-103 are withdrawn. Claims 75, 85-87, and 91-94 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
Acknowledgement is made of Applicant’s National Stage entry of PCT Application PCT/US19/56996 filed on October 18, 2019, and Applicant’s claim to benefit of provisional application no. 62/747961, filed on October 19, 2018.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/22/2025 has been entered.
Election/Restrictions
Response to Election/Restriction Requirement
In a response filed on 3/29/2024, Applicant elected with traverse, Amyotrophic Lateral Sclerosis (ALS), as the species of disease/disorder to which all claims shall be restricted if no generic claim is finally held to be allowable. Applicant further identified that the provisionally elected species read on claims 75, and 85-87. Claims 76-81 have been cancelled in a response filed on 08/30/2024. Newly added claims 95-103 are also withdrawn for not reading on the elected ALS species.
Regarding the claims to which the elected species reads on and Applicant’s traversal of said election, Applicant argues on p. 1 of Response to Election/Restriction, filed on 3/29/2024, that:
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In response to Applicant’s traversal, the technical feature linking the claims is the claimed compound 6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-1 0,11 -diol (apomorphine):
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As detailed in the following prior art rejection, the technical feature linking the claims is not a special technical feature, because it does not make contribution over the prior art. Therefore, the technical feature linking the claims does not constitute a special technical feature under PCT Rule 13.2. Accordingly, the claims lack unity of invention, and restriction is proper and is made final.
Claim Interpretation
Regarding amended claim 75, “A method of activating heat shock protein factor 1 (HSF1) in a subject, comprising administration of a therapeutically effective amount of... wherein the method treats…”, the preamble here merely recites an intended use results that does not result in a structural difference between the claimed invention and the prior art. As discussed below, the prior art teaches a method of treating ALS comprising administering a therapeutically effective amount of (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo[de,g]quinoline-10,11-diol to a subject. Statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. MPEP § 2111.02.
A preamble generally is not limiting when the claim body describes a structurally complete invention such that deletion of the preamble phrase does not affect the structure or steps of the claimed invention. In the instant case, there is no structural difference between the claimed invention and the prior art as both methods comprise the administration of a therapeutically effective amount of (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo[de,g]quinoline-10,11-diol to a subject in the treatment of ALS, for example.
Applicant’s amended claim 75 is broadly interpreted as a method of treating any of the claimed diseases, including ALS, by administering a therapeutically effective amount of (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo[de,g]quinoline-10,11-diol to a subject, activating HSF1 in a subject.
Activating HSF1 in a subject is not considered to be further limiting of the positively recited process step of administering a therapeutically effective amount of (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo[de,g]quinoline-10,11-diol to a subject. The preamble of claim 75 therefore recites a result of performing the method of treatment, when S(+)-apomorphine is administered, and as such is not considered to be further limiting of the claim from which it depends.
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 75, 85-87, and 91-94 are rejected under 35 U.S.C. 103 as being unpatentable over Inoue et al., (2017), EP 3 246 046 A1, (“Inoue”), in view of Chin et al., (2015), WO 2015/070156 A1 (“Chin”), and Lehmann et al., European Journal of Pharmacology, Vol. 88, pp. 81-88 (1983), (“Lehmann”; Cited on Applicant’s 8/30/2024 IDS), McGown et al., (2014), SITraN (Dept. of Neuroscience); Ph. D. Thesis (2014), and Feneberg et al., Mol Neurobiol 55, 7789–7801 (02/2018) (“Feneberg”).
Regarding claim 75, the amended claim recites:
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Inoue teaches the use of “a prophylactic and/or therapeutic agent for amyotrophic lateral sclerosis (ALS), which contains one or more kinase inhibitors selected from a group consisting of ….”, “… apomorphine…” (i.e., the claimed compound) (Inoue Abstract, claim 14). The claimed compound is disclosed on p. 78, ll. 25 as:
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Inoue also discloses on p. 71, paragraph [0084]:
The prophylactic and/or therapeutic agent for ALS of the present invention can be administered orally or parenterally in the form of the active ingredient the compound of the present invention as it is alone, or as a pharmaceutical composition in an appropriate dosage form blended with a pharmacologically acceptable carrier, excipient, diluent and the like.
While Inoue describes a general dosage for oral administration of the claimed compound (i.e., at least 0.1 mg (suitably 0.5 mg) to at most 1000 mg (suitably 500 mg) to an adult 1 to 6 times per day) in paragraph [0086], Inoue does not expressly disclose administering a therapeutically effective amount of apomorphine to a subject in need thereof.
Chin teaches administering a therapeutically effective amount of apomorphine to a subject in need thereof. Chin teaches an oral solid dosage form of the instantly claimed compound that is administered to a patient in need thereof, comprising the range of about 0.1 to about 100 mg or about 2 to about 6 mg of apomorphine (p. 16, and Example 18):
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Both Inoue (p. 78, ll. 25) and Chin (p. 16) disclose apomorphine structurally as:
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However, the claimed compound, although used in the same capacity for treatment of ALS as disclosed by Inoue, is represented structurally as:
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A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. That is, "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." MPEP §2144.09 (I). More specifically, compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious). MPEP §2144.09 (II).
The two compounds are considered to be stereoisomers, specifically enantiomers, and are of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. Thus, "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." MPEP §2144.09 (I). Additionally, obviousness does not require absolute predictability, but a reasonable expectation of success. See MPEP 2143.02.
Inoue, teaches on p. 71 that “When the compound of the present invention contains isomers such as an optical isomer, a stereoisomer, a regioisomer, or a rotamer, any one of the isomers and mixtures are also encompassed in the compound of the present invention” (para, [0073]), and that “These isomers can be obtained as single products by a synthesis method, a separation method (e.g., concentration, solvent extraction, column chromatography, recrystallization etc.), an optical resolution method (e.g., fractional recrystallization, chiral column method, diastereomer method etc.) and the like each known per se” (para, [0074]).
While Inoue and Chin do not expressly teach the claimed (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo[de,g]quinoline-10,11-diol compound, Lehmann teaches a motivation for selecting S(+)-apomorphine over R(-)-apomorphine. Lehman teaches that “S(+)-apomorphine has an approximately ten-fold lower affinity for presynaptic dopamine receptors compared to R(−)-apomorphine.” (Abstract). That is, the use of S(+)-apomorphine in the treatment of ALS, is reasonably expected to have less side effects that are typically associated with dopamine agonism, as a result of the use of R(−)-apomorphine.
This is further underscored by McGown’s (2014) teachings. McGown on page 87 teaches about the enantiomers of apomorphine, and states that “ApoS has been highlighted recently as a potential treatment for ALS (Mead et al 2013) whereas ApoR was identified primarily as a treatment for Parkinson’s disease as it is a potent dopamine agonist unlike ApoS (Kempster et al 1990)…”. On page 95, McGown teaches “Apomorphine S, unlike the R enantiomer, is not a dopamine agonist and does not activate the dopamine receptors at 25 times the concentration required by Apomorphine R (Saari & King 1973). Both the S and R enantiomers have a known antioxidant activity and both have been shown to directly scavenge reactive oxygen species (Gassen et al 1996) …”.
Therefore, it would have been prima facie obvious, for one of skill in the art to formulate a method of treating ALS in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo[de,g]quinoline-10,11-diol to the subject. One would have been motivated to do so, with reasonable expectation of success because Inoue teaches a prophylaxis and/or treatment of ALS, by administering apomorphine (i.e., as a racemic mixture or as singular isomers) (p. 71, para [0073]; pp. 72-73, paragraph [0090] and [0091]; Abstract: [0105]) for use as a therapeutic for the treatment of ALS (Abstract); Chin teaches the administration of apomorphine to a subject in need thereof; and Lehmann teaches that that the “S(+)-apomorphine has an approximately ten-fold lower affinity for presynaptic dopamine receptors compared to R(−)-apomorphine”, and as such, is expected to have less side effects that are typically associated with dopamine agonism. While both stereoisomers are included as options for use as treatment of ALS in a subject in need thereof according to Inoue in view of Chin, Lehmann specifically teaches that the S(+)-stereoisomer of apomorphine would not cause side effects that are typically associated with dopamine agonism because, "[i]t is known that the R(-)-stereoisomer of apomorphine possesses high affinity agonistic properties at dopamine receptors, which no such activity has been found for the S(+)-stereoisomer (Saari et al., 1973).". This is underscored by McGown’s teachings as discussed above.
As such, there is sufficient motivation for one of skill in the art reading Inoue, Chin Lehmann and McGown, to formulate a method of treatment for ALS in a subject in need thereof, using the S(+)-stereoisomer of apomorphine, and arrive at the claimed invention successfully. Claim 75, a method of treatment of ALS, by administering a therapeutically effective amount of S(+)-apomorphine to a subject, is obvious over Inoue, in view of Chin, and in further view of Lehmann and McGown. Additionally, obviousness does not require absolute predictability, but a reasonable expectation of success. See MPEP 2143.02.
The claimed method further discloses a result (i.e., “upregulating heat shock protein factor 1 in the subject”), by administration of a therapeutically effective amount of a pharmaceutical composition comprising (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol to the subject, and wherein the disease of claim 75 is associated with a type of protein misfolding, accumulation, or aggregation.
Regarding the phrase, “A method of activating heat shock protein factor 1 (HSF1 in a subject …”, this is not considered to be further limiting of the positively recited process step. See Claim Interpretation. The phrase recites a result of performing the method of treatment, when S(+)-apomorphine is administered, and as such is not considered to be further limiting of the claim.
Nonetheless, McGown (2014) teaches in Abstract the use of a zebrafish model of ALS that overexpresses the mutant G93R SOD1 gene alongside a heat shock protein (HSP) hsp70-DsRed stress readout. “This has been used to demonstrate that the hsp70- DsRed readout is activated by sod1 toxicity and that in the embryo stages it is characterized by expression in the glycine positive inhibitory interneurons.”.
McGown further teaches throughout the disclosure that ALS involves proteins (like TDP-43, mutant SOD1) misfolding and clumping, and that HSF1 triggers HSPs to help refold or clear these toxic aggregates on pages 31-32, for example. On page 44, McGown also teaches that “Two thousand compounds from the Spectrum library were screened for NRF2 activation and S[+]-Apomorphine was identified. This was then taken into the SOD1G93A mouse model where CNS penetrance was shown, NRF2 induction was seen and attenuation of motor dysfunction occurred…”. McGown also discusses a known drug with a similar profile: “Arimoclomol is a drug which up-regulates the unfolded protein response (UPR) via activation of heat shock factor 1 (HSF1). HSF1 is present as 32 monomers with the inactive heat shock proteins, but upon cellular stress, trimerisation occurs and the HSF1 translocates into the nucleus and activates the heat shock response (Shamovsky & Nudler 2008)” at pages 31-32.
On page 87 teaches about the enantiomers of apomorphine, and states that “ApoS has been highlighted recently as a potential treatment for ALS (Mead et al 2013) whereas ApoR was identified primarily as a treatment for Parkinson’s disease as it is a potent dopamine agonist unlike ApoS (Kempster et al 1990)…”. On page 95, McGown teaches “Apomorphine S, unlike the R enantiomer, is not a dopamine agonist and does not activate the dopamine receptors at 25 times the concentration required by Apomorphine R (Saari & King 1973). Both the S and R enantiomers have a known antioxidant activity and both have been shown to directly scavenge reactive oxygen species (Gassen et al 1996) …”. To one of ordinary skill in the art, there’s reasonable motivation to explore S(+)-apomorphine’s impact on this pathway as well since HSF1 and HSPs are implicated in the treatment of ALS. Claim 75 is obvious over the cited prior arts.
Regarding claims 85-86, the claims recite: “The method of claim 75, wherein the therapeutically effective amount[[dose]] is administered to the subject as a dose of at least 0.12 mg/kg.”
As applied above, Inoue in view of Chin, and in further view of Lehmann and McGown, teaches the method of claim 75.
Inoue teaches a general dosage for the oral administration of the claimed compound (i.e., at least 0.1 mg (suitably 0.5 mg) to at most 1000 mg (suitably 500 mg) to an adult 1 to 6 times per day) in paragraph [0086]:
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Moreover, Chin also teaches an oral solid dosage form of the instantly claimed compound that is administered to a patient, comprising the range of about 0.1 to about 100 mg or about 2 to about 6 mg of apomorphine (p. 16).
Therefore, it would have been prima facie obvious, for one of ordinary skill in the art, at the time of filing, to claim a method of treating ALS comprising apomorphine, as disclosed by Inoue and Lehmann, and applied to claim 75, with the claimed oral range of administration of apomorphine specifically disclosed by Chin, and arrive at the claimed invention of: “The method of claim 75, wherein the therapeutically effective amount[[dose]] is administered to the subject as a dose of at least 0.12 mg/kg.”. One would have been motivated to do so, with reasonable expectation of success, because both Inoue and Chin discloses the use of apomorphine and a claimed oral range of about 0.1 mg to about 100 mg. The average human body weight is about 70 kg; therefore, the therapeutic amount ranges from about 1.43 µg/kg to about 1.43 mg/kg which fully encompasses the claimed range of about 0.12 mg/kg. Furthermore, it is within the skill of an artisan to routinely optimize and formulate the claimed range in order to arrive at the claimed invention with reasonable expectation of success. 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 85 is therefore also obvious over Inoue in view of Chin, and in further view of Lehmann and McGown.
Regarding claim 86, the claim recites: “(Currently Amended) The method of claim 75, wherein the therapeutically effective amount[[dose]] is administered to the subject as a dose of between 5 mg/day and 5000 mg/day.”.
Inoue in view of Chin, and in further view of Lehmann and McGown teaches the method of claim 75.
Regarding the limitation “…wherein the therapeutically effective amount[[dose]] is administered to the subject as a dose of between 5 mg/day and 5000 mg/day…”, Inoue teaches in paragraph [0086] that:
For oral administration, at least 0.1 mg (suitably 0.5 mg) to at most 1000 mg (suitably 500 mg) per dose for oral administration, or at least 0.01 mg (suitably 0.05 mg) to at most 100 mg (suitably 50 mg) per dose for parenteral administration, can be administered to an adult 1 to 6 times a day. The dose may be increased or reduced according to the symptoms.
Moreover, as disclosed and applied above to claim 85, both Inoue and Chin teach an oral solid dosage range of apomorphine from about 1.43 µg/kg to about 1.43 mg/kg, which fully encompasses the claimed range of about 0.12 mg/kg as required in claim 85; and that said dose “can be administered to an adult 1 to 6 times a day” (Inoue, paragraph [0086]). Furthermore, it is within the skill of an artisan to routinely optimize and formulate the claimed range in order to arrive at the claimed invention with reasonable expectation of success. 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 86 is therefore also obvious over Inoue in view of Chin, and in further view of Lehmann and McGown.
Regarding claim 87, the claim recites: “The method of claim 75, wherein the (6aS)-methyl-5,6,6a,7-tetrahydro-4Hdibenzo[de,g]quinoline-10, 11-diol is administered by oral administration.”
Inoue in view of Chin, and in further view of Lehmann and McGown teaches the method of claim 75.
As disclosed and applied to claim 85, both Inoue and Chin teach wherein apomorphine is administered orally. Claim 87, is therefore also obvious over Inoue in view of Chin, and in further view of Lehmann and McGown.
Regarding claim 91, the claim recites: “The method of claim 75, wherein the subject is a human subject.
Inoue in view of Chin, and in further view of Lehmann and McGown teaches the method of claim 75.
Regarding the limitation “… wherein the subject is a human subject…”, Inoue teaches that the compound can be administered to an adult 1 to 6 times per day (para [0086]), which one of skill in the art would reasonably expect to include an adult human.
Nonetheless, whereas Inoue does not expressly disclose that said adult is a human, Chin Example 18 teaches the administration of apomorphine to “healthy human volunteer subjects between the ages of 18 and 45 years…” (p. 47). Claim 91 is therefore also obvious over Inoue in view of Chin, and in further view of Lehmann and McGown.
Regarding claims 92-94, the claims recite a method of claim 75 wherein the ALS is associated with TDP-43 misfolding, accumulation and protein aggregation. Inoue in view of Chin and Lehmann and McGown teach the method of claim 75.
Inoue teaches that the compounds of the disclosure are medicaments effective for the treatment of ALS (p. 73, ll. 8-10), and teaches in exemplary embodiments, that “the effect of candidate medicaments on the motoneuron cells derived from ALS patients was studied using iPS cells derived from ALS patients having other gene mutation (SOD1, TDP-43 and C9orf72) and iPS cells derived from sporadic ALS patients.” (p. 79, [0096], ll. 34-36).
While Inoue teaches exemplary compounds from the list of medicaments as effective against ALS associated with SOD1 mutation, TDP-43 mutation, C9orf72 mutation and/or sporadic ALS (p. 79, [Table 5]), Inoue does not expressly disclose said association with S(+)-apomorphine, for example, against ALS associated with TDP-43 mutation, as part of its exemplary embodiments.
However, patents are relevant as prior art for all they contain, and “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). For example, "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994),” see MPEP 2123.
Nonetheless, Feneberg teaches that transactive response DNA binding protein (TDP-43) has long been characterized as a main hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (Abstract: “TDP-43 accumulates in nerve cells of nearly all cases of amyotrophic lateral sclerosis (ALS; the commonest form of motor neuron disease) and in the majority of Tau-negative frontotemporal lobar degeneration (FTLD)”), and that “Cytoplasmic neuronal and glial inclusions of TDP-43 are found in 98% of all cases of ALS and in the majority of Tau-negative frontotemporal lobar degeneration (FTLD-TDP) cases, typically behavioral variant frontotemporal dementia (FTD)” (p. 7789).
Therefore, it would have been prima facie obvious, for one of ordinary skill in the art, to further modify the teachings of Inoue, in view of Chin, and in further view of Lehmann and Feneberg, as discussed above, and arrive at a method whereby S(+)-apomorphine is used in a method of treating ALS in a subject wherein the ALS is associated with abnormal TDP-43 including misfolding, accumulation, or aggregation, and arrive at the claimed invention successfully. One of ordinary skill in the art would have been motivated to do so because Feneberg teaches that TDP-43 is found in 98% of all cases of ALS, thus arriving at the claimed invention per claim 75. Claim 75, is therefore obvious over Inoue, in view of Chin, and in further view of Lehmann, McGown, and Feneberg.
Applicant’s Arguments
Applicant’s Arguments against cited references
Applicant argues that the cited references do not teach or suggest activation of HSF-1. More specifically, Applicant contends that none of the cited references teach or suggest that S(+)-apomorphine is useful for the activation of the HSF-1 pathway, and that for at least this reason the cited claims are non-obvious over the prior art. Applicant’s Remarks at page 6. Applicant argues that the data in the application supports a finding that administration of S(+)-apomorphine can activate HSF1 regulated genes and that none of the cited prior art references teach this finding.
Examiner’s Response
Acknowledgment is made of Applicant’s arguments which have been fully considered; however, they were not found to be persuasive in view of the above rejections under 35 U.S.C. §103.
Applicant’s arguments that the cited prior art references do not teach that the administration of S(+)-apomorphine results in the upregulation of HSF1 regulated genes is not found to be persuasive in view of the above rejection of Inoue in view of Chin et al., (2015), WO 2015/070156 A1 (“Chin”), and Lehmann et al., European Journal of Pharmacology, Vol. 88, pp. 81-88 (1983), (“Lehmann”; Cited on Applicant’s 8/30/2024 IDS), McGown et al., (2014), SITraN (Dept. of Neuroscience); PhD Thesis (2014), and Feneberg et al., Mol Neurobiol 55, 7789–7801 (02/2018) (“Feneberg”).
The prior art references cited above not only teaches the claimed invention, but also suggest motivation to explore the upregulation of HSF1 regulated genes according to McGown teachings discussed above. "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). MPEP § 2112(I).
The Examiner respectfully submits that Inoue teaches a prophylactic and/or therapeutic agent for ALS [0001] selected from a closed group comprising the claimed apomorphine (p. 4, ll. 8). Inoue addresses the stereoisomerism of the compounds of the invention on p. 71, and asserts that “When the compound of the present invention contains isomers such as an optical isomer, a stereoisomer, a regioisomer or a rotamer, any one of the isomers and mixtures are also encompassed in the compound of the present invention” (para, [0073]), and that “These isomers can be obtained as single products by a synthesis method, a separation method (e.g., concentration, solvent extraction, column chromatography, recrystallization etc.), an optical resolution method (e.g., fractional recrystallization, chiral column method, diastereomer method etc.) and the like each known per se” (para, [0074]). There is suggestion and expectation here that the stereoisomer S(+)-apomorphine is also a prophylactic and/or therapeutic agent for ALS [0001].
Inoue also teaches, in exemplary embodiments, that “the effect of candidate medicaments on the motoneuron cells derived from ALS patients was studied using iPS cells derived from ALS patients having other gene mutation (SOD1, TDP-43 and C9orf72) and iPS cells derived from sporadic ALS patients” ([0096]).
Regarding administering a therapeutically effective amount, Inoue does not expressly disclose administering a therapeutically effective amount of apomorphine to a subject in need thereof.
Chin teaches administering a therapeutically effective amount of apomorphine to a subject in need thereof as discussed above.
While Inoue and Chin do not expressly teach the claimed (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo[de,g]quinoline-10,11-diol compound, Lehmann teaches that the “S(+)-apomorphine has an approximately ten-fold lower affinity for presynaptic dopamine receptors compared to R(−)-apomorphine.” (Abstract). That is, the use of S(+)-apomorphine in the treatment of ALS, is reasonably expected to have less side effects that are typically associated with dopamine agonism, as a result of the use of R(−)-apomorphine.
This is underscored by McGown’s teachings about S(+)-apomorphine, as well as potential implications of its administration on HSF1.
Therefore, it would have been prima facie obvious, for one of skill in the art to formulate a method of treating ALS in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising (6aS)-6-methyl-5,6,6a,7-tetrahydro-4H- dibenzo[de,g]quinoline-10,11-diol to the subject. One would have been motivated to do so, with reasonable expectation of success because Inoue teaches a prophylaxis and/or treatment of ALS, by administering apomorphine (i.e., as a racemic mixture or as singular isomers) (p. 71, para [0073]; pp. 72-73, paragraph [0090] and [0091]; Abstract: [0105]) for use as a therapeutic for the treatment of ALS (Abstract); Chin teaches the administration of apomorphine to a subject in need thereof; and Lehmann teaches that that the “S(+)-apomorphine has an approximately ten-fold lower affinity for presynaptic dopamine receptors compared to R(−)-apomorphine”, and as such, is expected to have less side effects that are typically associated with dopamine agonism. While both stereoisomers are included as options for use as treatment of ALS in a subject in need thereof according to Inoue in view of Chin, Lehmann and McGown specifically teaches that the S(+)-stereoisomer of apomorphine would not cause side effects that are typically associated with dopamine agonism because, "[i]t is known that the R(-)-stereoisomer of apomorphine possesses high affinity agonistic properties at dopamine receptors, which no such activity has been found for the S(+)-stereoisomer (Saari et al., 1973).".
As such, there is sufficient motivation for one of skill in the art reading Inoue, Chin Lehmann and McGown, to formulate a method of treatment for ALS in a subject in need thereof, using the S(+)-stereoisomer of apomorphine, and arrive at the claimed invention successfully.
While Inoue in view of Chin, Lehman, and McGown does not expressly teach the administration of S(+)-apomorphine against ALS associated with, for example, TDP-43 mutation, as part of its exemplary embodiments, patents are relevant as prior art for all they contain, and “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). For example, "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994),” see MPEP 2123.
Nonetheless, Feneberg teaches that transactive response DNA binding protein (TDP-43) has long been characterized as a main hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (Abstract: “TDP-43 accumulates in nerve cells of nearly all cases of amyotrophic lateral sclerosis (ALS; the commonest form of motor neuron disease) and in the majority of Tau-negative frontotemporal lobar degeneration (FTLD)”), and that “Cytoplasmic neuronal and glial inclusions of TDP-43 are found in 98% of all cases of ALS and in the majority of Tau-negative frontotemporal lobar degeneration (FTLD-TDP) cases, typically behavioral variant frontotemporal dementia (FTD)” (p. 7789).
Therefore, it would have been prima facie obvious, for one of ordinary skill in the art, to further modify the teachings of Inoue, in view of Chin, and in further view of Lehmann and McGown, as disccussed above, and arrive at a method whereby S(+)-apomorphine is used in a method of treating ALS in a subject wherein the ALS is associated with abnormal TDP-43 including misfolding, accumulation, or aggregation, and arrive at the claimed invention successfully, similarly to the exemplary embodiments disclosed by Inoue above. One of ordinary skill in the art would have been motivated to do so because Feneberg teaches that TDP-43 mutation is found in 98% of all cases of ALS. Considering that apomorphine has been demonstrated by Inoue as one of the compounds for treating ALS (p. 78, [Table 4-5], ll. 25), there is reasonable expectation that the specific S-apomorphine would also be successful. Additionally, obviousness does not require absolute predictability, but a reasonable expectation of success. See MPEP 2143.02.
Moreover, as discussed above, the two compounds are considered to be stereoisomers, specifically enantiomers, and are of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. MPEP §2144.09 (I). The use of S(+)-apomorphine in the treatment of ALS, is reasonably expected to have less side effects that are typically associated with dopamine agonism as a result of the use of R(−)-apomorphine as discussed above by Lehmann. Lehman’s teaching is underscored by Applicant’s Declaration showing that R(-)-apomorphine has a higher EC50 than S(+)-apomorphine.
Furthermore, Applicant’s specification (para [0044]) does not make any distinction between the two enantiomers of apomorphine and their ability to significantly impact protein misfolding, accumulation of misfolded proteins, and protein aggregation:
[0044] The present invention is predicted on the surprising finding, demonstrated through screens and tests, that 6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol is a potent HSF1 activator and can significantly impact protein misfolding, accumulation of misfolded proteins, and protein aggregation.
Applicant’s argument that the claimed stereoisomer is a potent HSF1 activator and can significantly impact protein misfolding, accumulation of misfolded proteins, and protein aggregation of TDP-34, which is associated with amyotrophic lateral sclerosis, is also not found to be persuasive. In the absence of evidence to the contrary, showing that this property is different between R(-)-apomorphine and S(+)-apomorphine, the burden is on applicants to show that this property is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989). Both stereoisomers activate HSF1. The only difference shown, based on Applicant’s Declaration, is a difference in EC50; however, the underlying mechanism of action and target receptor binding remains the same, thus possessing similar structural and functional characteristics.
In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
The prior arts of record clearly show that the claimed invention is obvious over Inoue in view of Chin and in further view of Lehmann, McGown and Feneberg, and as such, claims 75, 85-87 and 91-94 are rejected. The rejection is maintained as final.
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 75, 85-87, and 91-94 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10, 17, and 18 of U.S. Patent No. US 11459301 B2 (“’301”) in view of Feneberg et al., Mol. Neurobiol. 55, 7789–7801 (2018) (“Feneberg”).
Although the claims at issue are not identical, they are not patentably distinct from each other because, for example, claims 17 and 18 of ‘301 disclose:
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The instant claims are also directed to a method of treating the same disease or disorder, in a subject in need thereof, using the same compound of ‘301 (i.e., a specific stereoisomeric form) (see, for e.g., instant claim 75).
The difference between, for example, the amended instant claim 75 and the claims of ‘301, is the recitation of a result associated with a positively recited process step (i.e., “the method comprising upregulating heat shock protein factor 1 in the subject by administration of…” S-apomorphine that is not considered to be further limiting, and the limitation of wherein the ALS is associated with abnormal TDP-34.
However, patents are relevant as prior art for all they contain, and “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). For example, "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994),” see MPEP 2123. Additionally, obviousness does not require absolute predictability, but a reasonable expectation of success. See MPEP 2143.02.
Nonetheless, Feneberg teaches that transactive response DNA binding protein (TDP-43) has long been characterized as a main hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (Abstract: “TDP-43 accumulates in nerve cells of nearly all cases of amyotrophic lateral sclerosis (ALS; the commonest form of motor neuron disease) and in the majority of Tau-negative frontotemporal lobar degeneration (FTLD)”), and that “Cytoplasmic neuronal and glial inclusions of TDP-43 are found in 98% of all cases of ALS and in the majority of Tau-negative frontotemporal lobar degeneration (FTLD-TDP) cases, typically behavioral variant frontotemporal dementia (FTD)” (p. 7789).
Therefore, it would have been prima facie obvious, for one of ordinary skill in the art, to further modify the teachings '301, in view of Feneberg, as disclosed above, and arrive at a method whereby S(+)-apomorphine is used in a method of treating ALS in a subject wherein the ALS is associated with abnormal TDP-43 including misfolding, accumulation, or aggregation, and arrive at the claimed invention successfully. One of ordinary skill in the art would have been motivated to do so because Feneberg teaches that TDP-43 is found in 98% of all cases of ALS, thus arriving at the claimed invention per claim 75.
Claims 75, 85-87, and 91-94 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 7 of copending Application No. 17633150 (reference application) (“’150”), in view of Gitler et al., (2017), Disease Models & Mechanisms (2017) 10, 499-502 (“Gitler”) and Feneberg et al., Mol Neurobiol 55, 7789–7801 (2018) (“Feneberg”).
Although the claims at issue are not identical, they are not patentably distinct from each other because, for example, independent claim 1 of ‘150 discloses:
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Whereas, the instant claims are directed to a method of treating a disease or disorder in a subject in need thereof using the same compound of ‘150 (see, for e.g., instant claim 75).
Claims 1, 4 and 7 of co-pending application teaches a method of treating neurodegenerative diseases (i.e., the genus), using the instantly claimed compound, S-apomorphine.
While the co-pending claims do not expressly disclose “amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, or Friedreich’s ataxia…” as neurodegenerative diseases, Gitler teaches on p. 499 that said diseases are examples of neurodegenerative diseases: “Examples of neurodegenerative diseases are Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia and the spinocerebellar ataxias…” (p.499, Introduction).
Therefore, it would have been obvious for one of skill in the art to modify the method of broadly treating neurodegenerative diseases as taught by co-pending claims 1, 4 and 7 of copending Application No. 17633150, to now include specific neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Huntington’s Disease and Friedreich’s Ataxia, in view of Gitler, and arrive at the instant claims successfully. One would have been motivated to do so, with reasonable expectation of success because, claims 1, 4 and 7 of copending Application No. 17633150 teaches a method of broadly treating a genus of neurodegenerative diseases (i.e., the genus), using S-apomorphine.
Gitler teaches the broad genus of neurodegenerative diseases to include diseases such as Huntington’s disease, ALS, and frontotemporal dementia and the spinocerebellar ataxias. It would have therefore been reasonable for one of skill in the art, to expect that the method of treatment in the co-pending claims could also be used in a method treatment for specific species of neurodegenerative diseases, as taught by Gitler.
Furthermore, the amended instant claim 75 and the claims of ‘150, differ in the recitation of a result associated with a positively recited process step (i.e., “the method comprising upregulating heat shock protein factor 1 in the subject by administration of…” S-apomorphine that is not considered to be further limiting, and the limitation of wherein the ALS is associated with abnormal TDP-34.
However, patents are relevant as prior art for all they contain, and “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). For example, "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994),” see MPEP 2123. Additionally, obviousness does not require absolute predictability, but a reasonable expectation of success. See MPEP 2143.02.
Nonetheless, Feneberg teaches that transactive response DNA binding protein (TDP-43) has long been characterized as a main hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (Abstract: “TDP-43 accumulates in nerve cells of nearly all cases of amyotrophic lateral sclerosis (ALS; the commonest form of motor neuron disease) and in the majority of Tau-negative frontotemporal lobar degeneration (FTLD)”), and that “Cytoplasmic neuronal and glial inclusions of TDP-43 are found in 98% of all cases of ALS and in the majority of Tau-negative frontotemporal lobar degeneration (FTLD-TDP) cases, typically behavioral variant frontotemporal dementia (FTD)” (p. 7789).
Therefore, it would have been prima facie obvious, for one of ordinary skill in the art, to further modify the teachings ‘150, in view of Feneberg, as disclosed above, and arrive at a method whereby S(+)-apomorphine is used in a method of treating ALS in a subject wherein the ALS is associated with abnormal TDP-43 including misfolding, accumulation, or aggregation, and arrive at the claimed invention successfully. One of ordinary skill in the art would have been motivated to do so because Feneberg teaches that TDP-43 is found in 98% of all cases of ALS, thus arriving at the claimed invention per claim 75.
Claims 75, 85-87 and 91-94 of the instant application are therefore obvious over claims 1, 4 and 7 of copending Application No. 17633150 in view of Gitler and Feneberg, as claims 75, 85-87 and 91 of the instant application teaches a method of treating specific types of neurodegenerative diseases (i.e., the species) using the same compound of the co-pending claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 75, 85-87, and 91-94 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 24 of copending Application No. 17633143 (reference application) (“’143”) in view of Inoue et al., (2017), EP 3 246 046 A1, (“Inoue”), Chin et al., (2015), WO 2015/070156 A1 (“Chin”), Lehmann et al., European Journal of Pharmacology, Vol. 88, pp. 81-88 (1983), (“Lehmann”; Cited on Applicant’s 8/30/2024 IDS), McGown et al., (2014), SITraN (Dept. of Neuroscience); PhD Thesis (2014), and Feneberg et al., Mol Neurobiol 55, 7789–7801 (02/2018) (“Feneberg”).
Although the claims at issue are not identical, they are not patentably distinct from each other because, for example, independent claim 1 of ‘143 discloses:
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However, claims 1 and 24 of the co-pending application do not immediately disclose a utility for the instantly claimed composition. Inoue, Chin, Lehmann, McGown and Feneberg’s teachings are discussed above.
Inoue discloses the use of “a prophylactic and/or therapeutic agent for amyotrophic lateral sclerosis (ALS), which contains one or more kinase inhibitors selected from a group consisting of ….”, “… apomorphine…” (i.e., the claimed compound) (Inoue Abstract, claim 14). The claimed compound is disclosed on p. 78, ll. 25 as:
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Inoue also discloses on p. 71, paragraph [0084]:
The prophylactic and/or therapeutic agent for ALS of the present invention can be administered orally or parenterally in the form of the active ingredient the compound of the present invention as it is alone, or as a pharmaceutical composition in an appropriate dosage form blended with a pharmacologically acceptable carrier, excipient, diluent and the like.
To one of ordinary skill in the art, it would have been obvious at the time of filing to combine the teachings of claims 1 and 24 of the co-pending application ‘143, in view of Inoue, and arrive at the claimed inventions of the instant application which is a method of treating a disease/disorder using apomorphine. One would have been motivated to do so, with reasonable expectation of success, because the combined teachings of copending application ‘143 and Inoue disclose a utility of apomorphine in treating a disease/disorder. Moreover, the comprising language of the instant claims pharmaceutical composition does not preclude the inclusion of a cyclodextrin.
Claims 75, 85-87 and 91-94 are therefore obvious over Claims 1 and 24 of copending application ‘143, in view of Inoue. This is a provisional nonstatutory double patenting rejection.
Applicant’s Arguments
Applicant argues that while they disagree with each of the above Double Patenting rejections supra, they are requesting that the rejections be held in abeyance until allowance of the present application or allowance of the respective co-pending applications.
Examiner’s Response
Applicant’s arguments are acknowledged and have been fully considered; however, they are not found to be persuasive in view of the rational presented supra. The rejections will therefore not be held in abeyance, and are maintained.
Pertinent Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Mead et al. Free Radical Biology and Medicine 61 (2013) 438–452 teaches “S[+]-Apomorphine, a receptor-inactive enantiomer of the clinically approved dopamine-receptor agonist (R[–]-apomorphine), was identified as a nontoxic Nrf2 activating molecule. In vivo S[+]-apomorphine demonstrated CNS penetrance, Nrf2 induction, and significant attenuation of motor dysfunction in the SOD1G93A transgenic mouse model of ALS. S[+]-apomorphine also reduced pathological oxidative stress and improved survival following an oxidative insult in fibroblasts from ALS patients. This molecule emerges as a promising candidate for evaluation as a potential neuroprotective agent in ALS patients in the clinic.” (Abstract). Considering information in the art, it would have been obvious to try S[+]-apomorphine against TDP-43 in view of Lehman’s teachings and the above discussed prima facie case including the cited references.
Conclusion
No claims are allowed.
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/C A/Examiner, Art Unit 1622 December 31, 2025
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622