Detailed Action
The present office action is in response to the application filed on 15 Dec 2022.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status
Claims 1-14 of the pending application have been examined on the merits.
Priority
Applicant identifies the instant application, Serial #: 18/010,690, filed 15 Dec 2022, as a National Stage Entry of International Patent Application #: PCT/US2021/029144, filed 26 Apr 2021, which claims priority from Provisional Application #: 63/044,515, filed 19 Jan 2020.
Response to Applicant Arguments
Acknowledgement is made of the remarks filed 09 Apr 2026.
The rejection of claims 1-14 under 35 U.S.C. § 112(a) is rendered moot following applicant amendments.
The rejection of claims 1-14 under 35 U.S.C. § 112(b) is rendered moot following applicant amendments.
The objection to claim 13 has not been overcome by applicant amendments. This objection is restated below.
Regarding the rejection of claims 1-2 under 35 U.S.C. § 103 over Jo et al. (Chem Biol, 2005, 12:703-715; provided in the office action mailed 09 Dec 2025), hereinafter Jo, further in view of Patani et al. (Chem Rev, 1996, 96:3147-3176; provided in the office action mailed 09 Dec 2025), hereinafter Patani, applicant's arguments filed 09 Apr 2026 have been fully considered but they are not persuasive.
On pg. 5 of the remarks, applicant argues that the office has not asserted a prima facie case of obviousness and that it has not met its burden of showing that a skilled artisan would be motivated to make the claimed compound as required by MPEP § 2144.09. Applicant argues that the artisan would not select SEW2898 as a lead compound for modification and that Jo clearly shows SEW2871 as the compound of interest (Remarks, pg. 6).
This is not persuasive. MPEP § 2144.09(I) states that a, “prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities.” MPEP § 2144.09(III) further states that, “structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious.” As stated in the office action mailed 09 Dec 2025, Jo explicitly teaches the swapping of the headgroups of SEW2871 to probe dipole moments and target interactions. Patani teaches that hydroxyl groups are a replacement for hydrogen to probe van der Waal’s radii and structure-activity relationships for various groups. SEW2898 has a H as the headgroup, and Patani teaches a viable method of replacing the H with an OH group to probe van der Waal’s radii and structure-activity relationships. There would further be an expectation for success which derives from the similarity of the chemical structures.
Applicant argues on pg. 6 of the remarks that nothing in Jo provides any motivation to the skilled person to modify the lead compound, SEW2898, to make any alternative compound, let alone the compounds presently claimed.
This is not persuasive. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See MPEP § 2145(IV). In this case, the rejection is made over Jo and Patani as stated above and in the office action mailed 09 Dec 2025.
Applicant argues on pg. 6 of the remarks that Patani is a comprehensive review detailing numerous strategies for bioisosterism in drug development and that there is no clear guidance by Jo or Patani that would lead the skilled person to specifically modify SEW2898 or SEW2871 to arrive at the instantly claimed compounds.
This is not persuasive. As stated in the office action mailed 09 Dec 2025, Jo explicitly teaches the swapping of the headgroups of SEW2871 to probe dipole moments and target interactions. Patani teaches that hydroxyl groups are a replacement for hydrogen to probe van der Waal’s radii and structure-activity relationships for various groups. SEW2898 has a H as the headgroup, and Patani teaches a viable method of replacing the H with an OH group to probe van der Waal’s radii and structure-activity relationships. This is the motivation to replace the H moiety of SEW2898 with the OH taught by Patani which is derived from the teachings of Jo and Patani.
Applicant argues on pg. 6 of the remarks that SEW2871 has limited clinical utility and that SEW2871 cannot be incorporated into a nanoliposomal formulation. Applicant argues that Compound I:
PNG
media_image1.png
110
266
media_image1.png
Greyscale
was developed to solve the issues of bioavailability and solubilization. Applicant argues that the ability of Compound I to be formulated in a manner that allows clinical delivery is a significant advance that could not have been predicted from either Jo or Patani or in combination. Applicant also argues that Compound 1 has better binding to the S1PR1 pocket than SEW2871, which could not have been predicted by the skilled artisan.
This is not persuasive. The ability to formulate a nanoliposome of the compounds was found to be obvious based on Gowda et al. (Mol Cancer Ther, 2014, 13:2328-2340; provided in IDS 12/09/24), hereinafter Gowda (2014) and Gowda et al. (Mol Cancer Ther, 2017, 16:440-452; provided in IDS 12/09/24), hereinafter Gowda (2017). Further, arguments are not a replacement where evidence is needed. See MPEP § 2145(I).
In light of the discussion above, the rejection of claims 1-2 under 35 U.S.C. § 103, as obvious over Jo and Patani is maintained for the reasons of record and restated below.
Regarding the rejection of claims 1-2 and 10-12 under 35 U.S.C. § 103 over Jo further in view of Patani and Marmonti et al. (bioRxiv, 2019, 805655; provided in the office action mailed 09 Dec 2025), hereinafter Marmonti, applicant arguments filed 09 Apr 2026 have been fully considered but are not persuasive.
Applicant argues on pg. 7 of the remarks that Marmonti does not make up for the deficiencies of Jo and Patani (see above) and does not make obvious the unexpected advantages of Compound I (see above).
See above for the response to the arguments against the prima facie case of obviousness over Jo and Patani that further apply to Jo, Patani, and Marmonti. Therefore, the rejection is maintained for the reasons of record above and restated below.
Regarding the rejection of claims 1-2 and 10-12 under 35 U.S.C. § 103 over Jo further in view of Patani, Marmonti, Gowda (2014), and Gowda (2017), applicant arguments filed 09 Apr 2026 have been fully considered but are not persuasive.
Applicant argues on pg. 7 of the remarks that Gowda (2014) and Gowda (2017) do not make up for the deficiencies of Jo, Patani, and Marmonti (see above) and does not make obvious the unexpected advantages of Compound I (see above).
See above for the response to the arguments against the prima facie case of obviousness over Jo and Patani that further apply to Jo, Patani, Marmonti, Gowda (2014), and Gowda (2017). Therefore, the rejection is maintained for the reasons of record above and restated below.
Claim Objections
Claim 13 is objected to because of the following typographic errors: The punctuation between items in the Markush group is not standardized. For instance, “melanoma” and “basal cell carcinoma” are separated with a comma and “hematopoietic cancers” and “testicular cancer” are separated by a semi-colon. Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jo and Patani.
The instant claims are drawn to a compound of Formula I (below) and compositions of a compound of Formula I and a pharmaceutically acceptable carrier:
PNG
media_image2.png
103
256
media_image2.png
Greyscale
Jo teaches three S1P1 receptor analogues, SEW2871, SEW2905, and SEW2898 (pg. 704, Fig. 1):
PNG
media_image3.png
228
625
media_image3.png
Greyscale
Jo teaches these compounds activated the S1P1 receptor with EC50 values of 107 ± 45 nM for SEW2905, 25 ± 23 nM for SEW2898, and 14 ± 8 nM for SEW2871 obtained using a GTPγ35S assay and teaches these compounds were diluted in buffer at various concentrations (pg. 708, columns 1-2; pg. 712, column 1). Jo further teaches that the swapping of the trifluoromethyl group for either the methyl group of SEW2905 or the hydrogen of SEW2898 was meant to examine the contributions of the trifluoromethyl group’s dipole moment on target receptor binding (pg. 707, column 1). However, Jo does not teach the compound of Formula I.
Patani teaches that bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents and the concept of bioisosterism is often considered to be qualitative and intuitive (pg. 3147, columns 1-2). Patani also teaches that there are opportunities to employ bioisosteres to gain specific insight into the quantitative structure-activity relationships associated with a specific class of drugs (pg. 3148, column 1). Hydroxyl groups are taught as replacements for hydrogen by Patani and that by probing the van der Waal’s radii of various substituents the medicinal chemist can effectively probe structure-activity relationships (pg. 3152, columns 1-2).
Based on the teachings of Jo and Patani, a person of ordinary skill in the art would modify the hydrogen of SEW2898, taught in Jo, with a hydroxyl group to perform structure-activity testing of various substituents with the S1P1 receptor, as taught by Patani, to arrive at the compound of instant Formula I. The artisan would further have to create dilutions of the compound with a pharmaceutically acceptable carrier of buffer to perform the tests, as taught by Jo. The artisan would be motivated to perform this bioisosteric change to gain specific insights into the quantitative structure-activity relationship of selective S1P1 agonists.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 1-2 and 10-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jo and Patani as applied to claims 1-2 above, further in view of Marmonti.
The instant application claims a method of decreasing vascular permeability in a subject in need by administering a compound of Formula I (claim 10), a method of treating diabetes or cancer by administering a compound of Formula I (claim 11), and a method of preventing or inhibiting metastasis of a cancer by administering a compound of Formula I (claim 12).
Jo teaches that the compounds SEW2871 and SEW2898 are potent S1P1 receptor agonists (see above), but does not teach the compound of Formula I. Patani teaches that hydroxyl groups can act as bioisosteres of hydrogen (see above). A person of ordinary skill in the art would find it obvious to replace the hydrogen of SEW2898 with a hydroxyl group to further probe structure activity relationship between the S1P1 receptor agonists taught by Jo and their target protein. However, neither Jo nor Patani teach treating cancer or increasing vascular permeability by administering a compound of Formula I.
Marmonti teaches that pharmacologic activation of the S1P1 receptor by SEW2871 repaired vascular hyperpermeability of Ewing sarcoma cells (pg. 2, Abstract; and pg. 4). Furthermore, Marmonti teaches that the activation of the S1P1 receptor improved tumor perfusion and reduced hypoxia which led to increased chemotherapeutic effect when SEW2871 was combined with doxorubicin to treat A673 cells (pg. 8; and Fig. 3).
Based on the teachings of Jo, Patani, and Marmonti, a person having ordinary skill in the art would use the compound of Formula I, as taught by Jo and Patani, and replace SEW2871 to determine if the greater chemotherapeutic effect remained when treating A673 cells with doxorubicin and SEW2871, as taught by Marmonti, and that SEW2871 would decrease vascular permeability of Ewing sarcoma cells. The artisan would have a reasonable expectation of success that this swap would work based on the close structural similarities of the compounds in question. See MPEP § 2144.09(II).
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 1-12 and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jo, Patani, and Marmonti as applied to claims 1-2 and 10-12 above, further in view of Gowda (2014), and Gowda (2017).
The instant application claims formulations which include the compound of Formula I in a nanoliposome where the nanoliposome comprises a phospholipid and a PEG-phospholipid (claim 3) where the phospholipid is ePC (claim 4) and the PEG-phospholipid is DPPE-PEG 2000 (claim 5). The instant claims further limit the ratio of the phospholipid:PEG-phospholipid to a molar percent ratio of 50:50 to 95:5 (claim 6) and further limits the molar percent ratio to 80:20 (claim 7). Additional limitations are found for the diameter of the nanoliposome ranging from 50 nm to 90 nm (claim 8), 60 nm to 80 nm (claim 9), or 65 nm to 75 nm (claim 14).
Jo teaches that the compounds SEW2871 and SEW2898 are potent S1P1 receptor agonists (see above), but does not teach the compound of Formula I. Patani teaches that hydroxyl groups can act as bioisosteres of hydrogen (see above). Marmonti further teaches that SEW2871 can produce greater than expected therapeutic effect when combined with doxorubicin for treating Ewing sarcoma (see above). A person of ordinary skill in the art would find it obvious to replace the hydrogen of SEW2898 with a hydroxyl group to further probe structure activity relationship between the S1P1 receptor agonists taught by Jo and their target protein. The artisan would further use the compound taught by Jo and Patani to replace SEW2871 to determine if the greater chemotherapeutic effect remained when treating A673 cells with doxorubicin and SEW2871, as taught by Marmonti. However, Jo, Patani, and Marmonti do not teach using a formulation that comprises the nanoliposome of the instant claims.
Gowda (2014) teaches that loading of drugs into nanoparticles to circumvent bioavailability, toxicity, or lethality can be used to overcome limitations of standard drug delivery systems while further being able to design the nanoparticles to optimize surface characteristics and size to increase circulation time and biodistribution (pg. 2328, column 2). Gowda further teaches that the enhanced permeability and retention effect of nanoparticles enables a higher accumulation in the target tumor than in normal tissues and that these lipid-based delivery systems have established track records with the ability to accommodate both hydrophilic and hydrophobic drugs (pg. 2328, column 2). Gowda teaches a novel PEGylated neutral liposomal system of an 80:20 mole percent ratio of ePC:DPPE PEG-2000 based on the size, zeta potential, efficacy, and stability of the target drug, leelamine (pg. 2331, column 2 to pg. 2332, column 1) and that this mole percent ratio was determined after testing various lipid ratios, including mole percent ratios of ePC:DPPE-PEG-2000 of 70:30, 72.5:27.5, 80:20, 85:15, and 90:10 and nanoliposome size ranges of 64.6 nm-70.2 nm (Table S2). Gowda (2014) further teaches the size of the engineered liposome was approximately 73.5 ± 4.42 nm when the drug was encapsulated (pg. 2332, Fig. 1).
Gowda (2017) teaches that one emerging research area to address drug resistance of cancer is screening for pharmacologic agents that synergize with one another to decrease the occurrence of resistant disease (pg. 440, column 1). Gowda (2017) teaches that nanoparticles can simultaneously deliver multiple agents to tumor cells to solve problems such as unique solubilities, bioavailability, toxicity profiles, drug compatibility, and increased costs due to FDA evaluation of multi-drug treatment regimens (pg. 440, columns 1-2). Gowda (2017) teaches the development of a nanoparticle to deliver celecoxib and plumbagin to synergistically kill melanoma cells. Gowda (2017) further teaches this nanoparticle is made of a 95:5 mole percent ratio of ePC:DPPE-PEG-2000 and that the size of the nanoliposome was 70.64 nm in saline when both drugs were encapsulated (pg. 441, column 2; and pg. 444, Fig. 1).
Based on the teachings of Jo, Patani, and Marmonti, a person having ordinary skill in the art would use the compound of Formula I, as taught by Jo and Patani, and replace SEW2871 to determine if the greater chemotherapeutic effect remained when treating A673 cells with doxorubicin and SEW2871, as taught by Marmonti, and that SEW2871 would decrease vascular permeability of Ewing sarcoma cells. The artisan would have a reasonable expectation of success that this swap would work based on the close structural similarities of the compounds in question. See MPEP § 2144.09(II).
Based on the teachings of Gowda (2014) and Gowda (2017), the artisan would create a formulation comprising the compound taught by Jo and Patani and doxorubicin to target Ewing sarcoma tumors, as taught by Marmonti. The artisan would encapsulate the combination of the compound of Formula I and doxorubicin in a nanoparticle of ePC and DPPE-PEG-2000 to solve the issues of unique solubilities, bioavailability, toxicity profiles, drug compatibility, and increased costs due to FDA evaluation of multi-drug treatment regimens, as taught by Gowda (2017).
The artisan would further experiment with the mole ratio percent of the nanoliposome composition to ensure that size, zeta potential, efficacy, stability, and loading efficacy of the drugs were accounted for with a reasonable expectation of success, including mole percent ratios of ePC:DPPE-PEG-2000 of 70:30, 72.5:27.5, 80:20, 85:15, and 90:10, as taught by Gowda (2014), to arrive at a nanoliposome with a diameter of 64.6 nm-70.2 nm, as taught by Gowda (2014).
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jonathan D. Mahlum whose telephone number is (703)756-4691. The examiner can normally be reached 8:30 AM - 5:00 PM ET, M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (571) 272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.D.M./Examiner, Art Unit 1625
/Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
Prosecution Insights