DETAILED ACTION
This Office action details a non-final action on the merits for the above referenced application No. Claims 1-19 are pending in this application.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a 35 USC 111(a) filing that claims benefit under 35 USC 121 as divisional of US application No. 16/839,544 filed on 3 Apr. 2020, which claims benefit under 35 USC 119(e) to US provisional application No. 62/829,982 filed on 5 Apr. 2019.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 13 Mar. 2024 has been considered.
Claim Rejections - 35 USC § 112
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 11, and 16-18 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. Instant claim 11 is dependent to genus claim 1 and requires that the compound exhibits at least 80% serum stability for about 120 min post synthesis when contacting human serum. Instant claims 16-18 are dependent to genus claim 15 and require the following (i) differentiating between diseased cells, (ii) the compound has higher uptake in the diseased cells compared to the healthy cell, and (iii) the compound have about 1.5-fold to about 3-fold higher cellular uptake in the diseased cells compared to the healthy cells.
[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54. The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. In this case the specification does not provide sufficient description of the species of formula (I) capable of satisfying the above limitation. As discussed in this Office action, the specification describes [18F]KS1 and [18F]KS2 as capable of satisfying the above limitations. However, outside of [18F]KS1 and [18F]KS2, a person of ordinary skill in the art would not know which species out of the thousands of other species encompassed by the claimed formula satisfy the above limitations.
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 1-19 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.
In claims 1, 13 and 15, the recitations of “(e.g., DOTA, NOTA and DFO)” and “(e.g., Cl, Br, F, I)” are indefinite because it is not clear if the recitations are merely examples or required limitations. Claims 2-12 depend claim 1 and fall therewith. Claim 14 depends to claim 13 and falls therewith. Claims 16-19 depend to claim 15 and fall therewith.
In claim 16, the recitation of “wherein the method can differentiate between diseased cells and healthy tissue” is indefinite because it is not clear how a method, which is a series of steps, can differentiate between things. Claims 17-18 depend to claim 16 and fall therewith.
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) 1-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rumsey et al. (J. Biol. Chem.; published 1999; see IDS filed on 13 Mar. 2024), in view of Kniess et al. (Med. Chem. Commun.; published 2015; see IDS filed on 13 Mar. 2024) and Gazivoda et al. (Carbohydrate Res.; published 2006; see IDS filed on 13 Mar. 2024), in further view of Yamamoto et al. (Nucl. Med. Biol.; published 1996; see attached 892).
Rumsey et al. teach the specificity of ascorbate analogs for ascorbate transport (see title). Rumsey et al. teach that ascorbate serves as a primary role in the defense of oxidant radicals in vivo. An ideal compound to study transport and accumulation would be specific for mechanisms of ascorbate transport only and would show no activity toward dehydroascorbic acid transport mechanisms (see pg. 232215). Rumsey et al. teach 6-deoxyphenyl-L-ascorbic acid
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, 6-deoxy(3-trifluoro)phenyl-L ascorbic acid
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, and 6-deoxychloro-L-ascorbic acid
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(see pgs. 23216 and table 1). A series of 6-deoxy-L-ascorbic acid analogs all inhibited ascorbate transport (see pg. 23217). Rumsey et al. teach [125I]6-deoxy-6-iodo-L-ascorbic acid (see pg. 23217). The ability to distinguish ascorbate transport from dehydroascorbic acid transport with a specific analog would be a useful tool. Unlike ascorbic acid, the 6-deoxy-6-haloascorbate analogs when oxidized cannot form a stable cyclic hemiketal structure in solution because the absence of a free 6-OH group. Oxidized 6-halo analogs, including [125I]6-deoxy-6-iodo-L-ascorbate should not be transported by mechanisms that transport dehydroascorbic acid (see pg. 23220). [125I]6-deoxy-6-iodo-L-ascorbate and its oxidized product are not transported by either glut1 or glut3-mediated mechanisms of DHA, irrespective of the oxidation state of the analog (see pg. 23221). 6-deoxy-L-ascorbic acid can be used to characterize the specific contribution of ascorbate transport pathways to total intracellular ascorbate accumulation (see pg. 23222).
Rumsey et al. do not teach a compound of formula (I)
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wherein R1 = Ph substituted with -X(CH2)m-R3 where X=O, m=0 or 1, and R3=18F or 11C or R1=Cl, n=1, and R2 = Ph substituted with -X(CH2)m-R3 where X=O, m=0 or 1, and R3=18F or 11C.
Gazivoda et al. teach the synthesis, structural studies and cytostatic evaluation of 5,6-di-O-modified L-ascorbic acid derivatives (see title). Gazivoda et al. teach that the 6-chloro derivative of 2,3-di-O-benzyl-L-ascorbic acid showed the best cytotoxic activity against all cell tested malignant tumor cells (IC50 = ~ 18µM) (see abstract). Gazivoda et al. teach compound 13
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(see scheme 1). Gazivoda et al. teach that among all the compounds evaluated for their cytotoxic activity, the 6-chloro derivative of 2,3-di-O-benzyl-L-ascorbic acid 13 showed the best cytostatic effects against all tumor cells (see conclusion). Gazivoda et al. teach the following cell lines MCF-7 (breast carcinoma), and MIaPaCa-2 (pancreatic carcinoma) (pg. 441). Gazivoda et al. teach that each test point was performed in quadruplicate in three individual experiments (see pg. 442). Gazivoda et al. teach that these reactions involve a two-step reaction pathway in which the first step is an E2 elimination reaction that produces exocyclic allylic tosylate, which then undergoes an SN2 reaction with the corresponding nucleophile to give 11 and 13 with the corresponding nucleophile to give 11 and 13 and in the next step the hydrolysis product 12 (see pg. 434).
Kniess et al. teach 2-[18F]fluoroethyl tosylate as a versatile tool for building 18F-bases radiotracers for PET (see title). Kniess et al. teach that the phenyl group is a recurrent functionality in a variety of biomolecules and is ideally suited for the introduction of radionuclides such as 11C as [11C]methyl via [11C]MeI or 18F as [18F]fluoroethyl via [18F]FETs (see pg. 1719). Kniess et al. teach that the phenolic groups are preferred to react with [18F]FETs. Regioselective [18F]fluoroethylation can be achieved by character of the added base, otherwise selective protective group may be used (see pg. 1750). Kniess et al. teach specific activities as high as 74 GBq µmol-1 and 92 GBq µmol-1 (see pgs. 1732 and 1726).
Yamamoto et al. teach positron labeled antioxidant 6-deoxy-6-[18F]flouro-L-ascorbic acid having developed 6-deoxy-6-[18F]fluoro-L-ascorbic acid as positron labeled analog of ascorbic acid for biokinetic studies on oxidative damages by PET. 18F-DFA has a moderate capability to accumulate in tumors. Oxygen derived free radical are involved in the pathogenesis of cerebral ischemic reperfusion injury. Ascorbic acid is one of the most potent antioxidants and free radical scavengers that act in the first line of defense (see pg. 479). Yamamoto et al. found that the increased uptake of 18F-DFA occurred in selectively vulnerable brain regions 5 days after the start of postischemic recirculation (see pg. 479).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the methods of Rumsey et al. (method of measuring ascorbate transport in cells, the method comprising contacting cells such as breast cancer cells or prostate cancer cells with an effective amount of one of 6-deoxyphenyl-L-ascorbic acid, and 6-deoxy(3-trifluoro)phenyl-L ascorbic acid) by measuring oxidative stress/detecting a ROS modulated illness/performing PET imaging wherein the measuring/detecting/performing involves contacting cells with or administering to a subject optionally having ischemia or cancer a 6-deoxyphenyl-L-ascorbic acid derivative having a -OEt18F group, or -O[11C]Me group at the phenyl moiety and a dehydrated 5-OH to form an
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or a -O[11C]Me derivative and optionally PET image/detect gamma radiation from the subject to differentiate diseased cells from healthy cells as taught by Gazivoda et al., Kniess et al., and Yamamoto et al. because it would have been expected to advantageously enable (PET) detection of oxidative stress associated ascorbate transport and/or ascorbate depletion in vitro or in vivo where the derivative advantageously cannot cyclize into a hemi-ketal DHA derivative whereby obviating DHA transport such as glut transport mechanisms.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the methods of Rumsey et al. (method of measuring ascorbate transport in cells, the method comprising contacting cells with an effective amount of 6-deoxychloro-L-ascorbic acid) by measuring oxidative stress/detecting a ROS modulated illness/performing PET imaging wherein the measuring/detecting/performing involves contacting cells, such as breast cancer cells or prostate cancer cells with or administering to a subject a derivative of compound 13 in Gazivoda et al. having a -OEt18F group at the phenyl moiety and a 4-OH to form
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and optionally PET image/detect gamma radiation from the subject optionally having ischemia or cancer as taught by Gazivoda et al., Kniess et al., and Yamamoto et al. because it would have been expected to advantageously enable PET detection of oxidative stress associated ascorbate transport and ascorbate depletion where the derivative has optimal hydrophilicity and advantageously cannot cyclize into a hemi-ketal DHA derivative whereby obviating DHA transport such as glut transport mechanisms.
Specific activity is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. See MPEP 2144.05.II. A person of ordinary skill in the art would have arrived at a specific activity of about 2,500 to about 4,000 mCi/µmol through routine experimentation in order to optimal mass ratio of the radiotracer administered.
The serum stability for about 120 min post synthesis when contacting human serum is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. A person of ordinary skill in the art would have arrived a compound that exhibits at least 80% serum stability for about 120 min post synthesis when contacting human serum through routine experimentation in order to arrive at an optimal serum stability for the compound during a PET scan for detecting ROS. Rumsey et al., Kniess et al. and Gazivoda et al. teach and make obvious [18F]KS1 and [18F]KS2, which the instant specification teaches exhibits at least 80% serum stability for about 120 min post synthesis when contacting human serum. A compound and its properties are inseparable.
The fold of higher cellular uptake in the diseased cells compared to the healthy cells is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. A person of ordinary skill in the art would have arrived at a compound that has about 1.5-fold to about 3-fold higher cellular uptake in the diseased cells compared to the healthy cells through routine experimentation in order to arrive at an optimal detection signal of disease cells in the subject. Rumsey et al., Kniess et al. and Gazivoda et al. teach and make obvious [18F]KS1, which the instant specification teaches exhibits a 2.2 -fold higher differential selectivity between the high and low ROS cell line and a 1.7-fold increased tumor uptake.
Claim(s) 1-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rumsey et al. (J. Biol. Chem.; published 1999; see IDS filed on 13 Mar. 2024), in view of Kniess et al. (Med. Chem. Commun.; published 2015; see IDS filed on 13 Mar. 2024) and Gazivoda et al. (Carbohydrate Res.; published 2006; see IDS filed on 13 Mar. 2024), and Yamamoto et al. (Nucl. Med. Biol.; published 1996; see attached 892), in further view of Halliwell (Annu. Rev. Nutr.; published 1996; see attached 892).
Rumsey et al. teach as discussed above.
Rumsey et al. do not further teach a method comprising measuring reactive nitrogen species.
Kniess et al. teach as discussed above.
Gazivoda et al. teach as discussed above.
Yamamoto et al. teach as discussed above.
Halliwell et al. teach that antioxidants are needed to prevent the formation and oppose the actions of reactive oxygen and nitrogen species, which are generated in vivo (see abstract, pg. 35, table 1). Excess NO. production is thought to be an important tissue injury mechanism in such conditions as chronic inflammation, stroke, and septic shock (see pg. 36). Ascorbate has several antioxidant actions in vivo and may react with NO2. (see pg. 6).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Rumsey et al. so that the method further comprises measure reactive nitrogen species in cells as taught by Halliwell et al. because it would have been expected to advantageously enable detecting the role reactive nitrogen species in diseases such as cancer, inflammation, and stroke.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN R DONOHUE whose telephone number is (571)270-7441. The examiner can normally be reached on Monday - Friday, 8:00 - 5:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached on (571)272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618