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
Applicants identify 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.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 15 Dec 2022 and 09 Dec 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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 § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Factors to be considered in making the determination as to whether one skilled in the art would recognize the applicant was in possession of the claimed invention as a whole at the time of filing include:
Actual reduction to practice;
Disclosure of drawings or structural chemical formulas;
Sufficient relevant identifying characteristics such as:
Complete structure,
Partial structure,
Physical and/or chemical properties, or
Functional characteristics when coupled with a known or disclosed correlation between function and structure;
Method of making the claimed invention;
Level of skill and knowledge in the art;
Predictability in the art.
While all these factors are considered, a sufficient number for a prima facie case are discussed below.
Regarding claims 1-3, here, the claims are drawn to "prodrug." Applicant provides no guidance as to prodrugs. The artisan understands that prodrug forms are generally determined a posteriori, and it is only through trial and error that prodrugs are identified. The artisan understands the concept of prodrugs, however the artisan does not per se understand what specifically describes a prodrug form. Han (AAPS Pharmsci, 2000, vol. 2, article 6), cited here for evidence, teaches there is no strict universal definition for a prodrug itself but that, in general, the prodrug is an inactivated form of the drug that activates in vivo to the active form (pg. 1, column 2). While some prodrugs are simply esters or salts, other prodrug forms are not chemically or structurally related to their active form, one example being glucose as the prodrug form of hydrogen peroxide (Table 1, pg. 5), as is hypoxanthine, thus posing a problem as to understanding what is the exact prodrug form of a compound, as hydrogen peroxide has two prodrug forms in the limited set of compounds exemplified in Han.
According to Ettamayer et al. (J Med Chem, 2004, 47:2393-2404), cited here for evidence, prodrugs are often accidental discoveries (pg. 2393, column 2). Furthermore, Testa et al. (Biochem Pharm, 2004, 68:2097-2106), cited here for evidence, teaches:
[A] number of challenges await medicinal chemists and biochemists carrying out prodrug research, such as the additional work involved in synthesis, physiochemical profiling, pharmacokinetic profiling and toxicological assessment. Two of these challenges are introduced here, namely biological variability and toxicity potential. The challenge of biological variety results principally but not only from the huge number and evolutionary diversity of enzymes involved in xenobiotic metabolism. Inter- and intra-species differences in the nature of these enzymes, as well as many other differences such as the nature and level of transporters, may render prodrug optimization difficult to predict and achieve. (pg. 2098, column 2)
Methods of making compounds, in general, are known to the artisan. However, the methods of making any specific prodrug are complex and poorly understood, requiring an undue amount of experimentation to determine if a compound is actually a prodrug, and the instant specification fails to provide guidance to overcome the complexity and difficulties known to the artisan, as discussed above.
Thus, the artisan would have increased difficulty in determining how to convert the claimed compounds into prodrugs.
Regarding claims 4-14, these claims are similarly rejected as these claims refer back to claims 1-3, but do not remedy the rationale underpinning the basis for rejecting claims 1-3.
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.") Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claims 12-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treatment of metastasis of a cancer in a subject, does not reasonably provide enablement for prevention of metastasis of a cancer in a subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
the quantity of experimentation necessary,
the amount of direction or guidance provided,
the presence or absence of working examples,
the nature of the invention,
the state of the prior art,
the relative skill of those in the art,
the predictability of the art, and
the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
Breadth of claims: The breadth of claims is drawn to methods of preventing or treating a metastasis of a cancer comprising administering a compound of formula I.
Nature of the invention: Claim 12 relates to a method for preventing or treating a metastasis of a cancer comprising administering a compound of formula I. Claim 13 further limits claim 12 by narrowing the types of cancers treated.
State of the prior art and level of predictability in the art: The state of the prior art is that the pharmacological art involves screening in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e., what compounds can treat which specific disease by what mechanism). There is no absolute predictability even in view of the seemingly high level of skill in the art.
Meyskens et al. (JNCI J Natl Cancer Inst, 2016, 108:djv309), hereinafter Meyskens, teaches that some types of cancer, such as breast cancer, are preventable, but the more widely accepted methods of prevention are lifestyle and environmental changes which should be considered as primary prevention. However, Meyskens also teaches that some cancers are stochastic and preventative measures may be futile (pg. 2). Meyskens further teaches that preclinical evaluation of chemopreventive agents is limited by the fact that many of the animal models to date have limited physiological relevance to human disease and that studies of possible preventive agents in multiple animal models are needed (pg. 5, column 1). Meyskens teaches that chemoprevention is not ready for routine adoption in cancer survivors and emphasis currently should be on primary prevention.
While some cancers are known to be preventable in the prior art, there is no nexus connecting cancer to the preventative treatments. Despite the high skill of the artisan, the unpredictability in the art of prevention leaves those skilled in the art with an undue burden of experimentation.
Level of one of ordinary skill: The artisans making and using Applicant's pharmaceutical compositions would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience. The level of skill in the art is high; however, due to the unpredictability in the pharmaceutical art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro or in vivo screening to determine which compounds exhibit the desired pharmacological activity and which diseases would benefit from this activity.
Amount of direction provided by the inventor and existence of working examples: Test assays and procedures are provided in pages 29-46 of the instant specification. Applicants have provided data showing the compound of Formula I is a S1P1 receptor agonist. However, the disclosure does not provide how the in vitro data model system or in vivo study correlates to the prevention of the cancers is claims 12-13.
Regarding the prevention of metastasis of cancer, there is no evidence of record which would enable the skilled artisan in the identification of the people who have the potential of becoming afflicted with the numerous diseases/disorders claimed herein. That a single compound can be used to treat or prevent metastasis by all cancers embraced by the claims is an incredible finding for which applicant has not provided competent evidence or discloses tests that are highly predictive for the pharmaceutical use for treating or preventing any or all of the diseases/disorders or conditions by administering the instant claimed compound.
Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved." See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
Quantity of experimentation needed to make or use the invention based on the content of the disclosure: The quantity of experimentation needed is undue experimentation. One of skill in the art would need to determine whether any of the instantly claimed types of cancers are actually preventable and/or preventable by an approach to the one instantly claimed. Furthermore, one of ordinary skill in the art would need to determine which patients not having particular cancer metastasis would otherwise develop it and administer the instant compound over such an extended period of time as to determine true prevention. Such a task has yet to be accomplished in the art and the instant specification provides no particular guidance on how to accomplish such a task.
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of ordinary skill in the art would have to engage in undue experimentation to prevent the types of cancers instantly claimed by using the compound recited in the instant claims, with no assurance of success.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1-14 are rejected as failing to distinctly claim the subject matter because the phrase “derivative thereof” in claims 1-3 is vague and indefinite. The term derivative is indefinite because it is unclear how far one can deviate from the parent compound without the “derivative” being so far removed as to be a completely different compound. Further, the specification fails to provide limiting examples or definitions which limit the phrase above and leave the skilled artisan unclear as to what a derivative may be. Claims 4-14 are rejected for referring back to claims 1-3 without providing remedy for the rationale underpinning the basis for rejecting claims 1-3. Applicant may overcome this rejection by deleting the phrase “or derivatives thereof” from the claims.
The term “about” in claims 6-9 and 14 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In claims 6-7 the term “about” renders the limitation of the composition of the nanoliposome indefinite. In claims 8-9 and 14 the term “about” renders the limitation of the size of the nanoliposome indefinite. Applicant may overcome this rejection by amending to delete “about” from the claims.
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 et al. (Chem Biol, 2005, 12:703-715), hereinafter Jo, and Patani et al. (Chem Rev, 1996, 96:3147-3176).
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:
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103
256
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Jo teaches three S1P1 receptor analogues, SEW2871, SEW2905, and SEW2898 (pg. 704, Fig. 1):
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228
625
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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 et al. (bioRxiv, 2019, 805655), hereinafter 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, and further in view of Gowda et al. (Mol Cancer Ther, 2014, 13:2328-2340; provided in IDS 12/09/2024), hereinafter Gowda (2014), and Gowda et al. (Mol Cancer Ther, 2017, 16:440-452; provided in IDS 12/09/2024), hereinafter 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.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Srinivasan et al. (Diabetes, 2008, 57:484-493) and Awad et al. (Kidney International, 2011, 79:1090-1098) are pertinent for teaching the effect of sphingosine 1-phosphate on diabetes and diabetic neuropathy.
Conclusion
No claim is allowed.
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.
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/J.D.M./Examiner, Art Unit 1625
/Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625