83Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 1-8 are pending in the application. Claims 1-8 are rejected.
Response to Amendment / Argument
The rejection of claim 2 under 35 USC 112(b) has been withdrawn in view of Applicant’s amendment.
Beginning on page 4 of the response, Applicant traverses the rejections of claims under 35 USC 103. Applicant summarizes the rejection and cites introductory case law on pages 4 and 5 of the response. Applicant refers to a lack of evidence that “Compound 3 would be more efficacious in reducing or attenuating neuroinflammation, amyloidopathy, or taupathy compared to the F12511 inhibitor of De La Torre.” First, there is no requirement that the prior art must suggest the same intended effect as Applicant, i.e. attenuating neuroinflammation, amyloidopathy, or taupathy. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Furthermore, there is no requirement that the prior art must suggest that the instant compound would be “more efficacious”.
Further on pages 6 and 7 of the response, Applicant refers to data found in Patoiseau. Applicant refers to testing found on page 10 and a lack of discussion regarding why “Compound 3 would be an optimum ACAT inhibitor for the treatment of Alzheimer’s disease.” As noted above, there is no requirement that the prior art must suggest the instant invention as the single best possible approach. See, for instance, MPEP 2123(II): “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).” Furthermore, the IC50 values do not correlate 1:1 with the cholesterol test reported in paragraph [0190] suggesting that it would be desirable to test multiple compounds in the various utilities thereof and not assume that the compound having the lowest IC50 should be pursued to the exclusion of all others in any particular utility.
On pages 7 and 8 of the response, Applicant cites various case law regarding combinations of references and states on page 8 that “Patoiseau, whether alone or in combination with Chang, fails to provide any guidance for specifically selecting Compound 3 for use in the treatment of any brain-related condition, let alone in the treatment of neuroinflammation, amyloidopathy, or taupathy.” As discussed above, the rejection is not premised on the notion that it would have only been obvious to apply compound 3 in additional utilities. The rejection is premised on an expectation that compounds having a reported property would be expected to be useful in utilities where said property has been disclosed as useful. Compound 3 happens to be one known compound with said property.
On pages 8 and 9 of the response, Applicant refers to the ability of the instant compound to permeate the blood-brain barrier and refers to the amendment to claim 1. Claim 1 only recites “said effective amount sustains ACAT inhibition” that does not recite any particular minimum level of inhibition. Furthermore, the data discussed relative to Figures 2A and Figure 3 were obtained using particular dosages that are not required in the instant claims. For instance, the specification states on page 31: “it was observed that both nanoparticle F12511 and nanoparticle F26 provided more than 95% enzyme inhibition (Fig. 2B).” While it may be the case that particular results can be obtained using F26 at a low dose relative to F12511, the instant claims are not limited to these embodiments. MPEP 716.02(d) states: “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”.
For these reasons, Applicant’s arguments regarding the rejection under 35 USC 103 are not found persuasive.
On page 10 of the response, Applicant traverses the double patenting rejection on the same basis as for 103 regarding sustain ACAT inhibition, which is not found persuasive for the reasons above.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 8 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 8 recites that ACAT activity in the brain of the subject is inhibited for at least 48 hours where claim 1 has been amended to recite “said effective amount sustains ACAT inhibition for at least 48 hours in the subject’s brain.” Accordingly, claim 1 appears to require some level of inhibition for 48 hours such that each embodiment embraced by parent claim 1 is also embraced by dependent claim 8 and the dependent claim fails to narrow the scope of embodiments embraced. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claim(s) 1-5, 7 and 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over De La Torre et al. Journal of Neuroscience Methods 2022, 367, 109437, which was published December 7th, 2021, in view of U.S. Patent PGPub No. 2015/0079161 A1 by Chang et al. and in further view of U.S. Patent PGPub No. 2006/0135785 A1 by Patoiseau et al.
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
De La Torre et al. teach that (abstract): “Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors have been considered as potential therapeutic agents to treat several diseases, including Alzheimer’s disease, atherosclerosis, and cancer.” The authors further teach “a simple method to encapsulate ACAT inhibitors, using the potent hydrophobic ACAT inhibitor F12511 as an example. By mixing DSPE-PEG2000, egg phosphatidylcholine (PC), and F12511 in ethanol, followed by drying, resuspension and sonication in buffer, we show that F12511 can be encapsulated as stealth liposomes at high concentration.” The authors teach the following in the conclusion section: “This new method will give researchers the opportunity to deliver ACAT inhibitors and other hydrophobic compounds/inhibitors at high concentrations as potential therapies to treat various human diseases, including AD. We also anticipate that by using DSPE-PEG2000 and PC based nanoparticles, the bioavailability and half-life of F12511 in vivo will be significantly increased (Allen et al., 1993).” Compound F12511 has the following structure:
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The compound DSPE-PEG2000 is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-[poly(ethylene glycol)-2000] (DSPE-PEG2000) as recited in claim 1.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art teaches nanoparticles (liposomes) where an outer portion comprises 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-[poly(ethylene glycol)-2000] and the core contains a structurally analogous compound relative to the compound of instant claim 1. The prior art teaches application in Alzheimer’s disease rather than the instantly claimed intended applications of “reducing or attenuating neuroinflammation, amyloidopathy or taupathy”.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2141.02)
Regarding the instantly claimed preamble, Chang et al. teach (title) “selectively inhibiting ACAT1 in the treatment of neurodegenerative disease”. The authors further teach that (paragraph [0015], page 3) “It has now been found that ACAT1, but not ACAT2, plays a significant role in amyloid pathology of AD in vivo.” Accordingly, a person having ordinary skill in the art would recognize Alzheimer’s disease as being characterized as an amyloidopathy. Furthermore, Chang et al. specifically teach that the compound of De La Torre et al. can be used in their method (page 4, Table 1, fourth entry). Chang et al. further teach that compounds having the following generic formula can be applied in their method on page 6:
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Since Chang et al. teach that ACAT1 inhibitors can be used in the treatment of Alzheimer’s disease and De La Torre et al. teach a method of improving delivery of ACAT inhibitors, a person having ordinary skill in the art seeking to optimize delivery of the compounds of Chang et al. would have been motivated to apply nanoparticle delivery.
Regarding the instantly claimed structure, Chang et al. do not particularly limit the structure of compounds; however, Patoiseau et al. teach compounds having (title) “an Acat Inhibiting Activity” including the following structure on page 5:
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The compound disclosed as a racemate would contain both stereoisomers including the structure instantly claimed. Regardless, Patoiseau et al. teach the analogous stereochemistry for compounds 1 and 2 on pages 3 and 4 such that a person having ordinary skill in the art would have expected the instantly claimed stereoisomer to be an ACAT inhibitor. Since the compound of Patoiseau et al. is similarly disclosed as an ACAT inhibitor and is structurally analogous to the compound of De La Torre et al., a person having ordinary skill in the art would have reasonably expected it to possess similar utility in treating Alzheimer’s disease and be similarly in need of delivery enhancement, i.e. via the nanoparticles of De La Torre et al. In the interest of determining an optimum ACAT inhibitor treatment for Alzheimer’s disease, a person having ordinary skill in the art would have been motivated to screen the additional known ACAT inhibitor of Patoiseau et al. in the nanoparticles of De La Torre et al. Such a method would be embraced by instant claims 1 and 7.
Regarding instant claim 2, De La Torre et al. teach the following on page 4:
[…] With 20 mol% (6 mM) PC, the nanoparticles were able to encapsulate approximately 40 mol% (12 mM) F12511; there is a large amount of F12511 detected in the supernatant, as well as in the corresponding eluted fractions from the column that co-elute with DSPE-PEG2000/PC (Fig. 2C). Based on several preparations of the nanoparticles made, after fractionation by centrifugation, the result of TLC analysis shows that there is approximately 9 mM of F12511 encapsulated, rather than the full 12 mM present in the unfractionated samples.
A person having ordinary skill in the art seeking to make a direct comparison would have been motivated to prepare analogous nanoparticles including where the ratio of ACAT inhibitor to PC is ~1.5:1 as embraced by instant claim 2.
Regarding instant claim 3, Chang et al. teach various methods of administration including intravenous and intraperitoneal. A person having ordinary skill in the art seeking to optimize delivery would have been motivated to test routine modes of administration including those taught by Chang et al.
Regarding instant claims 4 and 8 and the newly added limitation to claim 1 regarding sustained ACAT inhibition, Chang et al. teach the following on page 9:
A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required based upon the administration of similar compounds or experimental determination. For example, the physician or veterinarian could start doses of an agent at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. This is considered to be within the skill of the artisan and one can review the existing literature on a specific agent or similar agents to determine optimal dosing.
The instantly claimed results appear to be results obtainable by routinely optimizing the dosage or dosing frequencies as described by Chang et al. and/or effects that result due to the benefits of the nanoparticles of De La Torre et al. "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Regarding instant claim 5, at least the presence of phosphatidylcholine would be embraced by instant claim 5 as the second therapeutic agent since the target is not defined in claim 5.
Claim(s) 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over De La Torre et al. Journal of Neuroscience Methods 2022, 367, 109437, which was published December 7th, 2021, in view of U.S. Patent PGPub No. 2015/0079161 A1 by Chang et al. and in further view of U.S. Patent PGPub No. 2006/0135785 A1 by Patoiseau et al., as applied to claims 1-5, 7 and 8 above, and in further view of Cummings et al. Journal of Alzheimer’s Disease 2019, 67, 779-794.
Instant claim 6 further differs from the rationale above by specifying a particular second therapeutic agent. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Furthermore, Cummings et al. teach in the abstract: “Many clinical trials of single-agent therapies have failed to affect disease progression or symptoms compared with placebo. The complex pathophysiology of AD may necessitate combination treatments rather than monotherapy.” Accordingly, a person having ordinary skill in the art would have been motivated to test combinations with known agents for treating Alzheimer’s disease. Cummings et al. teach, for instance BACE inhibitors and Aβ monoclonal antibodies in Figure 1 on page for targeting the amyloid cascade, which are both embraced by instant claim 6 as β-secretase inhibitor and antibody, respectively.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-5, 7 and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 12,419,847. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the patent recite products instantly being used along with an intended use of the instantly claimed utilities. Claim 1 of the patent recites nanoparticles having the same structure and components instantly claimed (including instant claim 7) where dependent claim 3 of the patent recites the specific ACAT inhibitor of instant claim 1. Furthermore, claim 1 of the patent recites “for reducing or attenuating neuroinflammation, amyloidopathy or taupathy” which is the application instantly claimed. Regarding instant claim 2, clam 1 of the patent recites the instantly claimed ratio. Regarding instant claim 3, claim 6 of the patent recites the instantly claimed modes of administration. Regarding instant claims 4 and 8 and the newly added limitation of claim 1 regarding sustained ACAT inhibition, the instantly claimed results appear to be results obtainable by routinely optimizing the concentrations within the ranges of the patent. "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Regarding instant claim 5, at least the presence of phosphatidylcholine would be embraced by instant claim 5 as the second therapeutic agent since the target is not defined in claim 5.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 12,419,847 in view of De La Torre et al. Journal of Neuroscience Methods 2022, 367, 109437, which was published December 7th, 2021, and in further view of Cummings et al. Journal of Alzheimer’s Disease 2019, 67, 779-794. The rationale of claims 1-5, 7 and 8 is incorporated here by reference. Instant claim 6 further differs from the rationale above by specifying a particular second therapeutic agent.
De La Torre et al. teach that (abstract): “Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors have been considered as potential therapeutic agents to treat several diseases, including Alzheimer’s disease, atherosclerosis, and cancer.” The authors further teach “a simple method to encapsulate ACAT inhibitors, using the potent hydrophobic ACAT inhibitor F12511 as an example. By mixing DSPE-PEG2000, egg phosphatidylcholine (PC), and F12511 in ethanol, followed by drying, resuspension and sonication in buffer, we show that F12511 can be encapsulated as stealth liposomes at high concentration.” The authors teach the following in the conclusion section: “This new method will give researchers the opportunity to deliver ACAT inhibitors and other hydrophobic compounds/inhibitors at high concentrations as potential therapies to treat various human diseases, including AD. We also anticipate that by using DSPE-PEG2000 and PC based nanoparticles, the bioavailability and half-life of F12511 in vivo will be significantly increased (Allen et al., 1993).” Compound F12511 has the following structure:
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The compound DSPE-PEG2000 is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-[poly(ethylene glycol)-2000] (DSPE-PEG2000) as recited in claim 1. At least since the claims of the patent embrace the same subject matter as De La Torre et al., a person having ordinary skill in the art would have been motivated to apply the nanoparticles in the patent in the treatment of Alzheimer’s disease.
Regarding combinations, "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Furthermore, Cummings et al. teach in the abstract: “Many clinical trials of single-agent therapies have failed to affect disease progression or symptoms compared with placebo. The complex pathophysiology of AD may necessitate combination treatments rather than monotherapy.” Accordingly, a person having ordinary skill in the art would have been motivated to test combinations with known agents for treating Alzheimer’s disease. Cummings et al. teach, for instance BACE inhibitors and Aβ monoclonal antibodies in Figure 1 on page for targeting the amyloid cascade, which are both embraced by instant claim 6 as β-secretase inhibitor and antibody, respectively.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW P COUGHLIN whose telephone number is (571)270-1311. The examiner can normally be reached Monday - Friday, 10 am - 6 pm EST.
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/MATTHEW P COUGHLIN/Primary Examiner, Art Unit 1626
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