PRODRUGS OF FULVESTRANT

DETAILED ACTION 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 . This is a Final Office Action. Election/Restrictions Applicant's election with traverse of Group (I) in the reply filed on January 10, 2022 is acknowledged. Group (I), drawn to compounds of formula (I-A) and compositions thereof, embraced by claims 1-19 was elected by Applicant. Applicant also elected, with traverse, the following species: PNG media_image1.png 140 336 media_image1.png Greyscale and claims 1, 2, 7, 14, 17, 18 and 19 read upon the elected species. In summary claims 3-17, 20, 21 and 24 are pending and claims 7, 14, 17 and 24 are under consideration. Claims 3-6, 8-13, 15, 16, 20 and 21 are withdrawn. Priority Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) (PROVISIONAL) or 119(a) (FOREIGN) or under 35 U.S.C. 120 (CONT/CIP), 121(DIV), or 365(c) (WO) is acknowledged. Applicant still has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(a) as follows: The later-filed application must be an application for a patent application (the parent for an invention which is also disclosed in the prior application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994). The disclosure of the prior-filed applications, Application No. 201821047939 and Application No. 201821019542, fail to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for claims 7, 14, 17 and 24 of this application. The present formula (VII) in claim 7, specifically R12 defined as acyl, is not found in either prior-filed applications nor are the subformulas PNG media_image2.png 56 263 media_image2.png Greyscale from claims 14 and 17. The species in claim 24 is found in Application No. 201821047939. There may be other omissions as well. Thus, the effective filing date of the present claims 7, 14 and 17 is the international filing date of May 24, 2019 and December 18, 2018 for claims 24. 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 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. Claim Rejections - 35 USC § 103 The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action: (a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a). Claims 7, 14, 17 and 24 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Jiao et al. (US 20160060288) in view of Dosa et al. (ChemMedChem, 2013, 8, 1002-1011), Ferriz et al. (Current Pharmaceutical Design, 2010, 16, pp. 2033-2052), , Rautio et al. (Nature Reviews, 2018, 17, 559-587) and Rautio et al. (2) (Nature Reviews, 2008, 7, 255-270). The present application claims prodrugs of the drug fulvestrant as provided by formula (I-A): PNG media_image3.png 147 335 media_image3.png Greyscale , wherein A= H and R= P(O)(OR12)2 and CH2OP(O)(OR12)2, wherein R12 is H or the Na salt. The following is the structure of fulvestrant: PNG media_image4.png 159 477 media_image4.png Greyscale , which is excluded by proviso. The ‘288 reference teaches fulvestrant as an “estrogen receptor blocking agent in the treatment of postmenopausal advanced breast cancer which fails to respond to anti-estrogen therapy and which is estrogen receptor positive,” see page 1, paragraph 0002. The reference further teaches “Currently, many commercially available preparations of fulvestrant use oil as an excipient for the following two reasons. On the one hand, fulvestrant, which is of poor stability and easy to degrade, is generally stored at −20, and should not be stored at room temperature for too long, otherwise its purity would be affected. Although the mechanism of its degradation is not clear, it is generally believed that the main reason for affecting its stability lies in the presence of —OH at positions C-3 and C-17. Meanwhile, the presence of —OH at 3- and 17-positions increases the polarity of drugs and the stimulation of drugs on the gastrointestinal tract, thus it can only be prepared into injection. On the other hand, like other steroids, fulvestrant, which is difficult to be formulated due to certain physical properties, is a molecule with high lipophilicity and extremely low water solubility of about 10 ng/mL,” see page 1, paragraphs 0004-0005. The ‘344 reference teaches prodrugs of fulvestrant where either one or both OH groups are protected with an ester functionality, where the prodrugs are outside of the scope of the present claims. The ‘288 reference does not teach phosphate ester prodrug at the 3-position of the phenyl ring of the steroid core. Dosa et al. also teaches water-soluble prodrugs of ursodeoxycholic acid utilizing phosphate prodrugs, see abstract. The reference further states, “However, we were unable to test UDCA in these models because its limited aqueous solubility precluded the administration, preferably intravenously (iv) for these indications, of doses large enough to have an effect. This is unfortunate as UDCA is an FDA-approved drug in the U.S. with an excellent safety record in humans even when used for extended periods of time at high doses, making it a particularly attractive potential therapy. With this in mind, we set out to synthesize highly water-soluble prodrugs of UDCA. We chose to focus on synthesizing phosphate ester prodrugs as this modification often increases aqueous solubility by several orders of magnitude. There are several examples of this class of prodrugs already in clinical use, including prednisolone phosphate, fosphenytoin, and fosamprenavir,” see page 1002, right-hand column, see also page 1003, Scheme 1 for compound 3, and page 1004, Scheme 4 for compound 16. PNG media_image5.png 348 554 media_image5.png Greyscale The fused steroid core in the Dosa reference differ from the presently claimed fused steroid core in that ring A is a fused cyclohexyl and in the present compound is a fused phenyl ring. However, the phosphate esters are at the 3-position of the steroid core and were utilized in an attempt to overcome the low water solubility property of the compound. The Dosa reference does not teach fulvestrant with a phosphate ester prodrug at the 3-position of the phenyl ring of the steroid core but does teach a similar steroid compound with a phosphate ester prodrug at the 3-position of the steroid core. Ferriz et al. teaches “The phenolic hydroxyl group is one of the most common functional groups found in drug molecules such as narcotic agonists and antagonists, estrogens, neurotransmitters, anticancer agents or antibacterial agents, among others. However, phenolic drugs usually present limited bioavailability and thus limited affectivity. Due to their poor delivery characteristics caused by their metabolic instability, they are often subjected to extensive first pass metabolism and in general, non-lipophilic character results in poor biomembrane passage. Solubility limitations have been also frequently encountered in the development of commercial phenolic drugs. Alternatively, the presence of phenolic groups brings the possibility of prodrug approach which can result in effective, safe and efficient delivery of the parent drug to the systemic circulation and to the desired site of action,” see page 2033, first paragraph. The reference further teaches, “Phosphate ester prodrug approach has overcome numerous drug delivery problems of sparingly water soluble potential drugs. The phosphate moiety can be directly attached to the parent drug to form a phosphomonoester, which undergoes an alkaline phosphatase-catalyzed bioconversion in vivo to release the parent phenol drug and inorganic phosphate, or via a chemical linker such as oxymethyl spacer, usually used to increase the space around the enzymatically cleavable bond,” see page 2036, right-hand column, third full paragraph. Ferriz goes on to state the addition of the following phosphate groups to propofol, a low aqueous solubility drug, see compounds 12 (propofol) and 22 below. The reference goes on to state, “Although the 22 hypnotic dose (HD50) was found to be around 10 times larger than the HD50 values reported for 12, the PP lethal dose (LD50) was as well bigger in mice, rats and pigs; this implies lower hypnotic activity and lower toxicity so it would be possible to apply larger doses of 22 to achieve the same level of sedation as with 12… Fig. (7),” see page 2036-2037, bridged paragraph. PNG media_image6.png 162 159 media_image6.png Greyscale PNG media_image7.png 180 186 media_image7.png Greyscale Another example in the Ferriz reference is compounds 31 and 32, shown below, see pages 2038-2040. Ferriz states, “DP-TAT-59 (31) Fig. (11) is a practically insoluble analogue of tamoxifen, an antagonist of the estrogen receptor in breast tissue, therefore used in the treatment of breast cancer. In order to increase the solubility of 31, a phosphate prodrug strategy was developed. Miproxifene phosphate (TAT-59) (32) Fig. (11) was synthesized [66,67] and actually is in phase II-III trials. Surprisingly 32 showed unusual low solubility comparing to most phosphate esters freely soluble in water [68,69]. Despite the relatively low solubility of 32, its solubility and dissolution rate were much higher than those of the parent drug, making succeed the prodrug approach. The dephosphorylation in vivo of 32 was rather quick as it was shown in pharmacokinetic studies. The bioavailability of 31 after oral 32 dosing was 28.8% in rats and 23.8% in dogs. Furthermore, no intact prodrug was detected in plasma of either species. However, no bioavailability data have been published for humans.” PNG media_image8.png 297 564 media_image8.png Greyscale Ferriz further teaches a solubility increase of compound 33, 0.017 mg/mL at pH 1.2 and 1.75 mg/mL at pH 7.4 and 37C, to 30 mg/mL at both pHs for compound 34, shown below, see pages 2039 and 2040. PNG media_image9.png 169 554 media_image9.png Greyscale These are just several examples of phosphate prodrugs taught in the Ferriz reference. The Ferriz reference does not teach a phosphate ester prodrug at the 3-position of the phenyl ring of the steroid core but does teach a phenyl ring substituted with a phosphate ester prodrug. Rautio et al. teach a plethora of prodrugs, including phosphate esters, see 560, Figure 1, upper left-hand side. The reference further teaches fospropofol, compound 3 in Table 1, page 562, and tedizolid phosphate, compound 17 in Table 1, page 564, provided increase water solubiity for the base compound, see Table 1 for each compound and page 561, last paragraph on bottom right-hand column and page 566, bottom left-hand column. Rautio further teaches, “Prodrugs can be used to protect active drugs from this first-pass effect by masking a metabolically labile but pharmacologically essential functional group, such as a phenol, to avoid rapid metabolism. This strategy is effectively illustrated by bambuterol, which is a long-lasting prodrug of the bronchodilator and β2-adrenergic receptor agonist terbutaline. In bambuterol, two metabolically susceptible phenol moieties on terbutaline are protected by dimethylcarbamate promoieties designed to avoid rapid and extensive first-pass metabolism in the gut and liver,” see page 572, bottom right-hand column. The present compound has a hydroxy at the 3-position of the fused phenyl moiety, which may also be susceptible to rapid metabolism due to the first-pass effect. Rautio further teaches, “Aqueous solubility is one of the most important proper-ties, regardless of the administration route of a drug. For oral drug delivery, a drug with low solubility may face low and variable oral bioavailability, which leads to an unpredictable clinical response. Prodrug strategies to improve solubility for oral administration are simi-lar to those used for solubilizing drugs in aqueous for-mulations for parenteral administration,” see page 567, first paragraph, right-hand column. Rautio (2) teaches “Phosphate esters can increase the oral bioavailability of many poorly water-soluble drugs. They are especially useful for drug candidates that require a high dose and exhibit a dissolution-rate limited absorption28. Nearly all oral phosphate ester prodrugs are rapidly hydrolysed to the parent drug by endogenous alkaline phosphatases at the intestinal cell surface during absorption, leading to low prodrug concentrations in the systemic circulation. An example is a water-soluble phosphate ester miproxifene phosphate (TAT‑59; TABLE 2), the prodrug of DP‑TAT‑59 (Refs 28,66). The parent drug, DP‑TAT‑59, has low to moderate hepatic clearance (CLh) compared with the hepatic blood flow (Qh) in preclinical species66 and in humans67, and a low Eh in the rat (0.4) and dog (0.2). DP‑TAT‑59 is apparently not bioavailable in preclinical species owing to the ‘brickdust’ nature of this parent drug, with a solubility of less than 1 μg per ml68. After TAT‑59 prodrug dosing, DP‑TAT‑59 bioavailability was greatly enhanced to 28.8% in rats and 23.8% in the dog, and in human trials DP‑TAT‑59 showed dose-linear pharmacokinetics after TAT‑59 dosing,” see page 261, right-hand column, third full paragraph. See also page 258, Table 2, second row, where the aqueous solubility was increased by -1,000 fold by the addition of a phosphate ester. Therefore, it would be obvious to add a phosphaste ester group as a prodrug to the phenolic group of fulvestrant because Ferriz teaches said addition improves water solubility of phenolic drugs and Jiao teaches fulvestrant is highly lipophilic and has extremely low water solubility. Dosa teaches a similar compound where a phosphate ester was added at the 3-position of a nonaromatic steroid A ring and Rautio and Rautio (2) teaches phosphate prodrugs increase water solubility and oral bioavailability of the base compound. Thus, said claims are rendered obvious by Jiao et al., Ferriz et al., Dosa et al., Rautio et al. and Rautio et al. (2). Note: It is not appropriate to cite references in arguments without providing the location of the citations within each reference. Applicant asserts, “Applicants assert that the proviso which reads that only one of R12 is selected from alkyl and aryl, then another R12 substitution must be hydrogen, defines a narrow and distinct class of compounds.” To clarify, claim 7 states, “with a proviso that when one of R¹² is selected from alkyl and aryl, then another R¹² substitution is hydrogen.” The proviso applies when one of R12 is alkyl and aryl, then the other R12 is hydrogen. Applicant traverses by stating, “As discussed below, the cited references do not render the claimed invention obvious for the following reasons: 1. The cited art, alone or combined, does not teach or suggest every element of the claimed invention… The cited art, alone or combined, does not teach or suggest every element of the claimed invention. The claims specifically recite Formula (VII) compounds (claim 7) and enumerated compounds (claims 14, 17 and 24) that are not taught or suggested by the cited references. The claimed compounds share a key structural feature - a phosphate moiety at the 3-position. As acknowledged by the Office on pages 8, 9, and 12 Jiao et al., Ferriz et al., Dosa et al., do not teach a phosphate ester prodrug at the 3-position of the phenyl ring of the steroid core. (Emphasis in original). Rautio et al. (2008 and 2018) further does not teach a phosphate ester prodrug at the 3-position of the phenyl ring of the steroid core. Hence, the cited references alone or in combination simply do not teach or suggest every element of claims 7, 14, 17 and 24.” This is not persuasive. Indeed, Jiao et al., Ferriz et al., Dosa et al. and Rautio et al. (2008 and 2018) do not teach a phosphate ester prodrug at the 3-position of the phenyl ring of the steroid core. However, as noted in the rejection, Dosa et al. does teach a phosphate ester prodrug at the 3-position of a non-aromatic steroid core and Ferriz et al. teaches a phosphate prodrug ester on a phenyl ring. Thus, the combination is rendered obvious. Applicant further traverses by stating, “2. The rejection also fails under KSR v. Teleflex, 550 U.S. 398, 418 (2007), which requires both a reason to combine and a reasonable expectation of success… The rejection also fails under KSR v. Teleflex, 550 U.S. 398, 418 (2007), which requires both a reason to combine and a reasonable expectation of success. The Office's rationale that phosphate esters "increase solubility" and therefore "may increase bioavailability" is insufficient under KSR because the cited art repeatedly warns that phosphate prodrugs may fail due to precipitation, poor absorption, rapid metabolism, and poor bioconversion. These warnings negate any reasonable expectation of success and defeat the Office's motivation-to-combine rationale under KSR.” This is also unpersuasive. As noted in the rejection, the references provide sufficient teachings, suggestions and motivations, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, or some "objective reason" within the meaning of KSR Int'l v. Teleflex, Inc., to modify the reference or to combine teachings of the prior art to achieve the claimed invention. The Jiao reference teaches steroids, e.g. fulvestrant, are difficult to be formulated due to certain physical properties, e.g. high lipophilicity and extremely low water solubility. Dosa et al. teaches water-soluble prodrugs of ursodeoxycholic acid, a steroid, utilizing phosphate prodrugs. Ferriz et al. teaches phenolic drugs usually present limited bioavailability and thus limited affectivity with solubility limitations.. The reference further teaches, “Phosphate ester prodrug approach has overcome numerous drug delivery problems of sparingly water soluble potential drugs. Rautio teaches, “Aqueous solubility is one of the most important proper-ties, regardless of the administration route of a drug. For oral drug delivery, a drug with low solubility may face low and variable oral bioavailability, which leads to an unpredictable clinical response.” Rautio (2) teaches “Phosphate esters can increase the oral bioavailability of many poorly water-soluble drugs.” The combination of references provides a reasonable expectation of success and would be obvious to a person skilled in the art. Applicant further traverses by noting, “3. The references collectively teach away from the very approach Applicant successfully implemented… Jiao's teachings are directly contrary to the claimed invention, which provides orally bioavailable 3-phosphate prodrugs of fulvestrant. While Jiao et al. teach prodrugs of fulvestrant where either one or both OH groups are protected with an ester functionality, Jiao et al. sets out to make a better injectable and teaches that such compounds are to be administered by injection. In view of Jiao et al., a person having ordinary skilled in the art would not look to making a prodrug of fulvestrant for oral administration by modifying either one or both of the OH groups with an ester functionality. Jiao et al. therefore does not render the claimed compounds obvious and, in fact, teaches away from Applicant's approach.” This is unpersuasive. In response to Applicant’s remarks with regards to the Jiao reference, the present claims are drawn to compounds, not compositions and thus, the claims are not limited to a route of administration. Applicant further notes, “Ferriz et al. and Dosa et al. emphasize phosphate prodrugs primarily in parenteral contexts. Dosa's steroid core is structurally distinct from fulvestrant's fused phenyl A-ring. Dosa's phosphate esters were designed specifically for intravenous administration, not oral delivery. A person having ordinary skilled in the art would simply not look to Dosa et al. when making a prodrug of fulvestrant for oral administration as presently claimed. Ferriz et al. warns that phenolic drugs suffer from "limited bioavailability," "poor delivery characteristics," "extensive first-pass metabolism," and "poor biomembrane passage." Ferriz et al. further teaches that phosphate prodrugs may exhibit "unusual low solubility," "precipitation," "rapid dephosphorylation," and "no intact prodrug detected." These warnings would discourage a person skilled in the art from using phosphate esters for oral delivery of phenolic steroids such as fulvestrant. Dosa et al. and Ferriz et al. therefore teach away from Applicant's invention.” This is unpersuasive. In response to Applicant’s remarks with regards to the Ferriz reference, the present claims are drawn to compounds, not compositions and thus, the claims are not limited to a route of administration. Indeed, Ferriz warns that phenolic drugs suffer from "limited bioavailability," "poor delivery characteristics," "extensive first-pass metabolism," and "poor biomembrane passage," which is the reason for making the phenolic prodrugs. Applicant is correct that Dosa's steroid core is structurally distinct from fulvestrant's fused phenyl A-ring, which is the reason for the combination of references with Ferriz, which teaches drugs with a phosphaste ester on a phenolic ring. Applicant further notes, “Both Rautio references are general reviews of prodrug strategies. They do not disclose fulvestrant, nor do they disclose phosphate esters at the 3-position of fulvestrant's aromatic A-ring. Importantly, Rautio warns that oral phosphate prodrugs frequently fail, stating that "only a few phosphate prodrugs for oral administration have reached the market," and that highly ionic phosphate prodrugs may exhibit "suboptimal enzymatic bioconversion," "precipitation," "poor absorption," and "reduced bioavailability." These warnings discourage the very approach Applicant successfully implemented. Rautio teaches away from the claimed invention. In summary, as discussed above, Jiao et al. expressly teaches that fulvestrant "can only be prepared into injection" due to instability and gastrointestinal irritation associated with the 3-OH and 17-OH groups, which directly discourages oral administration. Ferriz et al warns that phenolic phosphate prodrugs suffer from poor bioavailability, precipitation, rapid dephosphorylation, and extensive first-pass metabolism, which directly discourages oral delivery. Dosa et al. teaches phosphate prodrugs specifically for intravenous administration, not oral use. Rautio et al. (2008 and 2018) warns that oral phosphate prodrugs frequently fail due to precipitation, poor absorption, and suboptimal enzymatic bioconversion, stating that only a few oral phosphate prodrugs have ever reached the market. These teachings collectively demonstrate that a person of ordinary skill would have been dissuaded from attempting an orally administered 3-phosphate prodrug of fulvestrant.” This is unpersuasive. In response to Applicant’s remarks with regards to the Rautio references, Both Rautio references are general reviews of prodrug strategies. They do not disclose fulvestrant, nor do they disclose phosphate esters at the 3-position of fulvestrant's aromatic A-ring. Importantly. Applicant has not provided the location in each reference for the citations beung argued. However, as noted previously, Rautio teaches, “Aqueous solubility is one of the most important proper-ties, regardless of the administration route of a drug. For oral drug delivery, a drug with low solubility may face low and variable oral bioavailability, which leads to an unpredictable clinical response.” Rautio (2) teaches “Phosphate esters can increase the oral bioavailability of many poorly water-soluble drugs.” The combination of references provides a reasonable expectation of success and would be obvious to a person skilled in the art. Moreover, a prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983). Applicant further traverses by contending, “4. In addition, Applicant provided rebuttal argument with experimental data which demonstrate unexpected results of exceptional magnitude. Secondary considerations further support non-obviousness… Applicant's experimental data demonstrates unexpected results of exceptional magnitude. The claimed 3-phosphate prodrugs (I-t and I-s) exhibit a 3,500-fold increase in aqueous solubility (17.1 µM) compared to fulvestrant (0.005 µM). This dramatic increase far exceeds the modest solubility improvements reported in the cited art and was not predictable from any reference. More importantly, oral administration of the claimed 3-phosphate prodrugs at a low dose (10 mg/kg) bypasses both the luminal precipitation trap and the Phase Il metabolic barrier that prevent oral absorption of fulvestrant. Fulvestrant itself shows no detectable plasma levels (ND) following oral dosing, whereas the claimed compounds deliver highly significant, therapeutically meaningful systemic exposure of active fulvestrant with measurable Cmax, AUC, and dose-linear pharmacokinetics. These results directly contradict the teachings of Jiao et al., Ferriz et al., Dosa et al., and Rautio et al. (2008 and 2018), and under In re Soni, 54 F.3d 746 (Fed. Cir. 1995), unexpected results that contradict the prior art overcome obviousness… As shown in Table 1 of the specification, compound (l-t) (disodium dihydrogen phosphate) and compound (I-s) (dihydrogen phosphate) exhibit a dramatic, unexpected 3500-fold increase in aqueous solubility (17.1 µM) compared to parent fulvestrant (0.005 µM)… The most convincing and legally dispositive evidence of non-obviousness is the in vivo pharmacokinetic data in beagle dogs comparing oral administrations (Table 2). PNG media_image10.png 197 633 media_image10.png Greyscale …, [O]ral administration of the claimed 3-phosphate prodrugs (l-t) and (I-s) at a lower dose (10 mg/kg) bypasses both the luminal precipitation trap and the Phase II metabolic barrier, delivering highly significant, therapeutic systemic exposure of active fulvestrant.” This is unpersuasive. Compound (i-s) is the elected species and used for the comparison to fulvestrant. Table 2 shows compounds (i-t) and (i-s), the phosphate esters have increased in vivo pharmakinetic activity over fulvestrant as noted in the table. This is not unexpected. As noted in the rejection above, making a phosphate ester of a low, water-soluble compound, will increase the water solubility, which in turn, will increase the bioavailability. Even if, arguendo, the results are considered unexpected, the claims are not commensurate in scope with the unexpected results. 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 non-obviousness 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). The non-obviousness of a broader claimed range can be supported by evidence based on unexpected results from testing a narrower range if one of ordinary skill in the art would be able to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof. In re Kollman, 595 F.2d 48, 201 USPQ 193 (CCPA 1979). Applicant further contends “Secondary considerations further support non-obviousness. Fulvestrant has been clinically limited for decades by its requirement for intramuscular injection. Clinicians and patients have endured the severe burden of painful, monthly, large-volume intramuscular depot injections creating a long-felt need for an orally bioavailable form to improve patient compliance and expand therapeutic use. Despite extensive research, others have failed to develop an oral fulvestrant formulation, and the cited art repeatedly warns that fulvestrant cannot be orally administered and that phosphate prodrugs frequently fail. Thus, the prior art remained completely unable to deliver an orally bioavailable form of the drug.” Establishing long-felt need requires objective evidence that an art recognized problem existed in the art for a long period of time without solution. The relevance of long-felt need and the failure of others to the issue of obviousness depends on several factors. First, the need must have been a persistent one that was recognized by those of ordinary skill in the art. In re Gershon, 372 F.2d 535, 539, 152 USPQ 602, 605 (CCPA 1967). Second, the long-felt need must not have been satisfied by another before the invention by the inventor. Newell Companies v. Kenney Mfg. Co., 864 F.2d 757, 768, 9 USPQ2d 1417, 1426 (Fed. Cir. 1988). Third, the invention must in fact satisfy the long-felt need. In re Cavanagh, 436 F.2d 491, 168 USPQ 466 (CCPA 1971). This is not persuasive. Regarding secondary considerations, Applicant has not provided any evidence that there was a persistent, distinct and unmet need based on the oral bioavailability of fulvestrant. Summary of Declaration under 37 CFR 1.132 by Dr. Purohit (filed on June 17, 2024).” This was addressed previously. Lastly to address the declaration, wherein the declaration provides data shown in Table 1 below that measures the thermodynamic solubility of compound (i-ak) and (i-s) compared to fulvestrant. PNG media_image11.png 146 380 media_image11.png Greyscale PNG media_image12.png 230 434 media_image12.png Greyscale PNG media_image13.png 298 624 media_image13.png Greyscale Compound (i-ak) was not discussed in the obviousness rejection and the declaration states said compound is provided for additional data, see Table 1. Compound (i-s) is the elected species and used for the comparison to fulvestrant. Table 1 shows compounds (i-ak, 1.32 mg.mL) and (i-s, 1.22 mg.mL), the phosphate esters are more soluble, approximately 1000-1100 times than fulvestrant, (0.0012 mg.mL). This is not unexpected. As noted in the rejection above, making a phosphate ester of a low, water-soluble compound, will increase the water solubility, which in turn, will increase the bioavailability. The declaration further contends, “Table-2 shown below shows bioavailability data of Fulvestrant after oral administration of Fulvestrant, compound (l-ak) and compound (I-s), where bioavailability of Fulvestrant was tested after compound (I-s), compound (l-ak), and Fulvestrant were given orally to beagle dogs (non-rodent), where Compound (I-s) and compound (I-z) tested are different compounds under different genus.” PNG media_image14.png 330 782 media_image14.png Greyscale Again, this is not unexpected. As noted above, phosphate prodrugs increase the water solubility, which in turn, may increase the bioavailability as also noted in the rejection. Even if, arguendo, the results are considered unexpected, the claims are not commensurate in scope with the unexpected results. 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 non-obviousness 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). The non-obviousness of a broader claimed range can be supported by evidence based on unexpected results from testing a narrower range if one of ordinary skill in the art would be able to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof. In re Kollman, 595 F.2d 48, 201 USPQ 193 (CCPA 1979). Therefore, the rejection is maintained. Applicant may request a pre-appeal conference to move forth with prosecution. Conclusion 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. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUSANNA MOORE whose telephone number is (571)272-9046. The examiner can normally be reached on Monday - Friday, 10:00 am to 7:00 pm. 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, Jeffrey Murray can be reached on 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see https://ppair-my.uspto.gov/pair/PrivatePair. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /SUSANNA MOORE/Primary Examiner, Art Unit 1624