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 .
Summary
Claims 15-36 are pending in this office action. Claims 1-14 are cancelled. All pending claims are under examination in this application.
Priority
The current application was filed on January 29, 2024 is a 371 of PCT/EP2022/071321 filed on July 29, 2022. The current application claims foreign priority to EP21306070.0 filed on July 30, 2021.
Information Disclosure Statement
Receipt of the Information Disclosure Statement filed on January 29, 2024 is acknowledged. A signed copy of the document is attached to this office action.
Claim Objections
Claims 15-31, and 34-36 are objected to because of the following informalities:
Claim 15: Please define the acronym “Ph” once in full. Thereafter, within the claims only the acronym needs to be stated.
Dependent claims 16-31 and 34 are included in this objection because they do not cure the defect of claim 15.
Claim 31: The claim preamble should be, “The pharmaceutical composition of claim 30…”.
Claims 35 and 36: The claim numbers are mislabeled as claim 32 and claim 33, respectively. [For examination purposes the second numbering of 32 will be examined as claim 35 and the second numbering of 33 will be examined as claim 36.]
Claim 35: Similar to claim 15, “Ph” needs to be defined. If this is addressed in claim 15, then “Ph” will be acceptable.
Claim 36: Furthermore, the chemical structures for XI-I are blurry. Also, E1 is not in the structures only E2 and E3-.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 36 [second numbering of claim 33] is 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.
Claim 36 fails to define the variables X and R. Therefore, the claim is unclear and indefinite.
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 non-obviousness.
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.
Claims 15-36 are rejected under 35 U.S.C. 103 as being unpatentable over Shaya et al. (WO2019/185901A1) over Fougere et al. (WO2019/016377A1), Fougere et al (WO2019/002505A1), and Hosseinimehr (Drug Discovery Today, 2007).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims. The Shaya et al. (WO2019/185901A1) reference was not attached to the office action due to the size of the document.]
1. Shaya et al.
Shaya et al. is the closest prior art to the present invention as it teaches pyclen-based macrocyclic ligands, chelates thereof and uses thereof (see title). Additionally, Shaya et al. disclose that the present invention relates to a ligand of Formula (A): or a carboxylate salt thereof; wherein Y1, Y2 and Y3 each independently represents -COOH or a picolinate of Formula (i): wherein each R1 independently represents a chromophore group; L1, L2 and L3 each independently represents a single bond or a linker; and X1, X2 and X3 each independently represents a hydrogen atom, a coupling function or a bio-vectorizing group. The present invention further relates to a process for manufacturing the ligand and to a process for manufacturing a chelate by means of complexation by the ligand of a rare-earth cation, preferably a lanthanide cation. The present invention further relates to the use of the ligand and/or the chelate in biological imaging and/or photoluminescence imaging (see abstract).
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2. Fougere et al.
Fougere et al. teach lipophilic macrocyclic ligands, complexes thereof, and uses of same (see title). In addition, Fougere et al. disclose that the present invention relates to novel lipophilic macrocyclic ligands, the complexes thereof, in particular radioactive complexes, and the uses of same in medical imaging and/or in therapy, in particular in interventional radiology (see abstract).
3. Fougere et al. ‘505
Fougere et al. ‘505 teach reinforced macrocyclic ligands, complexes thereof, and uses of same (see title). Furthermore, Fougere et al. ‘505 disclose that the invention relates to new macrocyclic ligands of formula (I) and complexes thereof, particularly radioactive complexes, and to the uses thereof and a method for preparing same. The ligands have a reinforced pyclene core (see abstract).
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4. Hosseinimehr
Hosseinimehr teaches foundation review: trends in the development of radioprotective agents (see title). Also, Hosseinimehr discloses that people may be exposed to ionizing radiation during radiotherapy or following exposure to radionuclides in nuclear medicine. Radioprotective agents have been used to reduce morbidity or mortality produced by ionizing irradiation. Early developments of such agents focused on thiol synthetic compounds, such as amifostine. This compound reduced mortality; however, there were difficulties in administering aminothiols that led to adverse effects. Hence, the development of radioprotective agents with lower toxicity and an extended window of protection has attracted much attention. Natural compounds have been evaluated as radioprotectants and they seem to exert their effect through antioxidant and immunostimulant activities. Although recent agents have lower efficacy, they have lower toxicity, more favourable administration routes and improved pharmacokinetics compared to the older thiol compounds (see abstract).
Combination of Shaya et al., Fougere et al., and Fougere et al. ‘505
Regarding instant claim 15, Shaya et al., Fougere et al., and Fougere et al. ‘505 teach a macrocyclic compound having medical applications. The necessary citations within Shaya et al., Fougere et al., and Fougere et al. ‘505 that pertain to instant claim 15 are presented in Table I.
Table I
Instant Claim 15
Shaya et al., Fougere et al., and Fougere et al. ‘505 Citations
A compound of the following general formula (I):
Shaya et al. disclose pyclen-based macrocyclic ligands, chelates thereof and uses thereof (see title, abstract, and claims within Shaya et al.).
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(see pages 6-7 within Shaya et al.).
Shaya et al. further disclose analogues of the following structure which are relevant to instant claim 1.
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(see page 9 within Shaya et al.).
Fougere et al. disclose lipophilic macrocyclic ligands, complexes thereof, and uses of same (see title, abstract, and claims within Fougere et al.). Additionally, Fougere et al. disclose acetylene derivatives off aryl groups on a similar macrocyclic structure as disclosed within Shaya et al.):
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(see page 15 within the original Fougere et al.). Where analogues can include variants of R3-5 of the following structures:
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(see pages 17-18 within the original Fougere et al.).
Finally, Fougere et al. ‘505 disclose reinforced macrocyclic ligands, complexes thereof, and uses of same (see title, abstract, and claims within Fougere et al. ‘505). Fougere et al. ‘505 disclose general structures such as:
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The macrocycles disclosed therein are relevant to instant claim 1 (see abstract and claims within Fougere et al. ‘505).
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It would have been obvious to one of ordinary skill in the art [skilled artisan; POSITA (person of ordinary skill in the art] prior to the effective filing date of the claimed invention to modify Shaya et al. and Fougere et al. ‘505 with the teachings of Fougere et al. to synthesize the necessary acetylene analogue in the 4-position (relative to the pyridine nitrogen). The motivation for doing so would have been to develop biological imaging agents or therapeutic agents using the extended acetylene substituents defined by Fougere et al.
Regarding instant claim 16, Shaya et al., Fougere et al., and Fougere et al. ‘505 teach the compound shown below:
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A skilled artisan (POSITA) using the teachings of Shaya et al., Fougere et al., and Fougere et al. ‘505 discussed within instant claim 15 and would incorporate the acetylene variant of Fougere et al.
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into the macrocycle disclosed by Shaya et al. to synthesize the desired derivative.
Please see the discussion and citations within instant claim 15 (Table I) for the necessary rejection text.
Regarding instant claims 17-19, Shaya et al., Fougere et al., and Fougere et al. ‘505 teach the use of a metal (M) and a radioelement used for chelation within the compounds of instant claims 15 and 16.
Shaya et al. disclose the use of metal cations (see page 47, lines 10-11 within Shaya et al.) such as Holmium (III), isotope 166Ho (see page 47, line 15 and page 49, line 27; both within Shaya et al.) and Terbium (III), isotope 149Tb (see page 47, line 14 and page 49, line 27; both within Shaya et al.).
Regarding instant claim 20, Shaya et al., Fougere et al., and Fougere et al. ‘505 teach the compound
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For the structure of the carbon and nitrogen backbone please see instant claim 16 for the necessary rejection text. Fougere et al. disclose the use of metal cations such as Yttrium (III) isotope 90Y (see paragraph [0103] and Example 8; both within Fougere et al.).
Regarding instant claims 21 and 26, Shaya et al., Fougere et al., and Fougere et al. ‘505 teach a pharmaceutical composition comprising the compound of instant claim 15 and one or more pharmaceutically acceptable excipient(s).
Shaya et al. disclose the use of one or more pharmaceutically acceptable excipient(s) (see page 11, lines 5-7 and page 48, lines 21-24; both within Shaya et al.).
Combination of Shaya et al., Fougere et al., Fougere et al. ‘505, and Hosseinimehr
Regarding instant claims 22 and 27, Shaya et al., Fougere et al., Fougere et al. ‘505, and Hosseinimehr teach the pharmaceutical composition wherein at least one of the pharmaceutically acceptable excipient(s) is a radioprotector.
Hosseinimehr discloses the pharmaceutical composition wherein at least one of the pharmaceutically acceptable excipient(s) is a radioprotector (see Table 1 for acceptable radioprotectors within Hosseinimehr).
Combination of Shaya et al., Fougere et al., and Fougere et al. ‘505
Regarding instant claims 23-24 and 28-29, Shaya et al., Fougere et al., and Fougere et al. ‘505 teach the pharmaceutical composition further comprising an iodinated oil and wherein the iodinated oil comprises ethyl esters of iodinated fatty acids of poppy oil.
Fougere et al. disclose the pharmaceutical composition further comprising an iodinated oil and wherein the iodinated oil comprises ethyl esters of iodinated fatty acids of poppy oil (see paragraphs [0131-0132] within Fougere et al.).
Regarding instant claim 25, Shaya et al., Fougere et al., and Fougere et al. ‘505 teach the compound
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A skilled artisan (POSITA) using the teachings of Shaya et al., Fougere et al., and Fougere et al. ‘505 discussed within instant claim 15 and would incorporate the acetylene variant of Fougere et al. into the macrocycle disclosed by Shaya et al. to synthesize the desired derivative. The acetylene derivative is a hybrid of both variants
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A skilled artisan (POSITA) could under routine conditions insert another acetylene after the aryl ring. Please also see the discussion and citations within instant claim 15 (Table I) for the necessary rejection text.
Regarding instant claims 30 and 31, Shaya et al., Fougere et al., and Fougere et al. ‘505 teach the compound
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For the structure of the carbon and nitrogen backbone please see instant claim 25 for the necessary rejection text. Fougere et al. disclose the use of metal cations such as Yttrium (III) isotope 90Y (see paragraph [0103] and Example 8; both within Fougere et al.).
Regarding instant claims 32 and 33, Shaya et al., Fougere et al., and Fougere et al. ‘505 teach a method for treating a cancer in a mammal in need thereof, the method comprising administering a therapeutically effective amount of the complex of instant claim 17 to the mammal.
Fougere et al. disclose a method for treating a cancer in a mammal in need thereof, the method comprising administering a therapeutically effective amount of the complex of instant claim 17 to the mammal [see paragraphs [0137-0138] and [0141-0146] within Fougere et al.; hepatocellular carcinoma (liver cancer)].
Regarding instant claim 34, Shaya et al., Fougere et al., and Fougere et al. ‘505 teach a method of medical imaging a patient, the method comprising administering an effective amount of the complex of instant claim 17 to the patient and conducting the medal imaging on the patient administered the complex.
Shaya et al. disclose a method of medical imaging a patient, the method comprising administering an effective amount of the complex of instant claim 17 to the patient and conducting the medal imaging on the patient administered the complex (see page 1, lines 7-10 and page 49, lines 5-26; both within Shaya et al.).
Regarding instant claims 35 and 36, Shaya et al., Fougere et al., and Fougere et al. ‘505 teach a process for the preparation of a compound having a general formula (I) of instant claim 15 proceeding through the desired intermediates:
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(see page 33 within Fougere et al. ‘505)
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(see page 35 within Fougere et al. ‘505). The synthetic methodology is disclosed by Fougere et al. ‘505 within pages 33-43 and see left side of the scheme above. The boxed structures are indicative of synthetic pieces that a skilled artisan would use for the process.
Installation of the appropriate acetylene derivative on the pyridine moiety could be realized through a pyridine iodide. For example, Sonogashira coupling with the corresponding pyridine iodide afforded the desired di-substituted acetylene in excellent yield.
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(see page 63 within Shaya et al.). All of the synthetic chemistry is within the literature for a skilled artisan (POSITA) to complete this process in sufficient yield.
A skilled artisan (POSITA) could synthetically install the desired substitution pattern for the overall process. Furthermore, this intermediate could be taken forward to the final product from I15, as shown above, by known chemistry presented in Shaya et al. Additionally, formation of the mesylate and in situ reaction to afford the iodide allows for incorporation of the pyridine functionality to the macrocycle. Simple global saponification will form the carboxylic acids.
Both the Sonogashira coupling and the mesylate formation followed by in situ reaction to afford the iodide, as shown above, would be employed at the appropriate time in the synthetic pathway. This methodology would ensure an efficient synthesis and process.
Analogous Art
The Shaya et al., Fougere et al., Fougere et al. ‘505, and Hosseinimehr are directed to the same field of endeavor as the instant claims, that is, a macrocyclic compound having medical applications, as disclosed within instant claim 1.
Obviousness Analysis
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the acetylene macrocycle disclosed by Shaya et al., using the teachings of Fougere et al., Fougere et al. ‘505, and Hosseinimehr in order to arrive at the subject matter of the instant claims.
The Shaya et al., Fougere et al., Fougere et al. ‘505, and Hosseinimehr references all have considerable application in the radioelement and macrocycle arts. In this instance, Shaya et al. and Fougere et al. ‘505 supply the synthetic template for the pyclen-based macrocycles, Fougere et al. supplies the extended acetylene variants, while Hosseinimehr supplies the support for the use of radioprotectors as excipients. All references are directed to the radioelement and macrocycle arts and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the four references when seeking to develop a series of pyclen-based macrocycle analogues.
Given these teachings, a POSITA would have been motivated to combine the pyclen-based macrocycle targets as disclosed by Shaya et al. and Fougere et al. ‘505, the extended acetylene variants disclosed within Fougere et al., and the support for the use of radioprotectors as excipients disclosed by Hosseinimehr.
The modification constitutes a simple substitution of one known element for another to obtain a predictable result [MPEP §2143(I)(B)].
The combination represents the use of a known technique to improve a similar composition in the same way [MPEP §2143(I)(C)].
The art provides a finite number of identified, predictable solutions, and the POSITA would have pursued the claimed configuration with a reasonable expectation of success [MPEP §2143(I)(E); KSR].
The combination of the pyclen-based macrocycles taught by Shaya et al. and Fougere et al. ‘505, along with the use of the necessary claim limitations taught by Fougere et al., and Hosseinimehr would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
Furthermore, the additional claim limitations taught by Fougere et al., Fougere et al. ‘505, and Hosseinimehr would have been viewed by a POSITA as routine design optimizations or known modifications for pyclen-based macrocyclic compounds. The motivation for doing so would have been to develop biological imaging agents or therapeutic agents using the extended acetylene substituents defined by Fougere et al. Implementing these features in Shaya et al.’s pyclen-based macrocyclic compounds would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Shaya et al., Fougere et al., Fougere et al. ‘505, and Hosseinimehr provides all the elements of the claimed invention. The resulting pyclen-based macrocyclic compositions, constitutes no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN W LIPPERT III whose telephone number is (571)270-0862. The examiner can normally be reached Monday - Thursday 9:00 AM - 5:00 PM.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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