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 .
Information Disclosure Statement
The information disclosure statements filed November 15, 2024, May 22, 2025, July 22, 2025, December 19, 2025, and April 24, 2026 are acknowledged and have been considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
Examples 2-9 on pages 9-14 and Experimental Examples 1-7 on pages 14-18 contain recitations of a unit describing the amount or concentration of radioactivity in a sample as “mci” and “mci/ml.” The examiner notes that the mci portion of these units is understood to represent millicuries. This unit is properly abbreviated with a capital “C” as mCi.
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.
Claim 14 is 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 treating a metastatic bone tumor in a subject using compounds of claim 1, does not reasonably provide enablement for imaging a metastatic bone tumor in a subject using the compounds represented by Formula I of claim 1 in the non-radiolabeled precursor form. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. These factors include, but are not limited to:
The breadth of the claims;
The nature of the invention;
The state of the prior art;
The level of one of ordinary skill;
The level of predictability in the art;
The amount of direction provided by the inventor;
The existence of working examples; and
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
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). To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, state and predictability of the art, and relative skill level
The invention of claim 14 relates to methods of both imaging and treating a metastatic bone tumor in a subject. This method involves administering an effective amount of the compound represented by Formula I of claim 1 to subjects in need thereof. This claim is drawn to a method of using a pharmaceutical compound for imaging purposes and therapeutic purposes.
The relative skill of those in the art who would use such compounds is high, likely that of one who has obtained at a Ph.D. or M.D.
In the art, it is well-understood that bisphosphonate compounds can effectively be used to treat metastatic bone tumors (Palma, E.; Bol. BioSyst., 2011 – provided by applicant in IDS filed December 19, 2025). The compound of Formula I in claim 1 is understood by the examiner to be a bisphosphonate compound. Furthermore, using bisphosphonate-containing compounds, and even bisphosphonate-chelator conjugates, for imaging metastatic bone tumors is also known in the art (Meckel, M., Nucl. Med. Biol., 2013 – provided by applicant in IDS filed July 22, 2025). However, the known methods of using bisphosphonate-chelator conjugates require a radionuclide to be coordinated by the chelating group in order for imaging to be performed. This is because the methods of imaging, such as PET and SPEC/CT require contract agents or tracer compounds possessing certain properties like radioactivity for signal to be obtained to generate the desired images of the metastatic bone tumors.
There is generally a lack of predictability in the pharmaceutical art. In re Fisher, 427, F. 2d 833, 166, USPQ 18 (CCPA 1970). However, regarding the properties of chemical compounds and their suitability for biomedical imaging techniques, predictability is high regarding certain aspects. It is understood that a compound lacking radionuclides will not emit sufficient radiation for detection by PET over background.
The breadth of the claims
Claim 14 is broad insofar as the claim includes in its scope both methods of treating and imaging metastatic bone tumors. Claim 14 is relatively narrow in that it requires the administration of compounds of Formula I of claim 1. An aspect of breadth though is that the compound of claim 1 does not require the additional presence of radionuclides.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides several examples of the use of radiolabeled forms of the compound of claim 1 for imaging metastatic bone tumors. However, the specification provides no examples or guidance for practicing the imaging method using non-radiolabeled forms of this molecule.
The quantity of experimentation necessary
Experimentation to determine ways to use non-radiolabeled forms of the compound of claim 1 for tumor imaging would be significant. As it is predictable that a non-radiolabeled molecule will not emit significant radiation for detection, it is not clear how a skilled artisan would determine how to successfully use a non-radiolabeled form of the compound of claim 1 to perform the method as claimed.
Because of the known state of the art, and in the absence of experimental evidence and working examples, it is apparent that the amount of experimentation required to determine how to use the non-radiolabeled forms of the compound of claim 1 to perform all of the claimed methods is very significant and unreasonable due to the known understanding of biomedical imaging techniques and the related imaging agent compound chemistry.
Accordingly, the instant claims do not comply with the enablement requirement of §112(a), since to practice the claimed invention in its “full scope,” a person of ordinary skill in the art would have to engage in an unreasonable amount of experimentation, with no reasonable expectation of success.
Claims 17 and 18 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 preparing the radiolabeled compound of claim 10 using radionuclide salt solutions containing , does not reasonably provide enablement for preparing the radiolabeled compound of claim 10 using radionuclide salts lacking the aforementioned radionuclides. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The Wands factors are as discussed above. These factors relate to claim 17 as follows:
The nature of the invention, state and predictability of the art, and relative skill level
The invention of claim 17 relates to a method of radiolabeling a bisphosphonate-DOTA conjugate compound with a radionuclide. This is a chemical synthesis method.
The relative skill of those in the art who would use such compounds is high, likely that of one who has obtained at a Ph.D. or master’s degree.
In the art of chemistry, it is well-understood that atoms are defined by their nuclei. While radioactive atoms can decay to form other atoms, this follows a very specific pathway of daughter atoms due to the forms of radiation emitted by a radionuclide. Furthermore, such changes depend on the half-life of the isotope, which can sometimes be exceedingly long. Thus, while it may be possible to convert between some radioisotopes, it is not possible for all radioisotopes to be used to convert to any possible radioisotope. Thus, it is understood that if a 225Ac radiolabel is desired, using a radionuclide salt containing 90Y or 32P will not produce the desired product.
Regarding the properties of chemical compounds and radioisotopes, the predictability is high regarding certain aspects. It is understood that not all radionuclides can be used to prepare all other radionuclides.
The breadth of the claims
Claim 17 is broad insofar as it includes in its scope using any radionuclide salt solution in the preparation of the radiolabeled compound of claim 10. While claim 10 requires the chelated radionuclide to be 68Ga, 177Lu, 225Ac, 64Cu, or 211At, the method as claimed allows for any radionuclide input for the reaction.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides several examples of the preparation of the radiolabeled compounds of claim 10. However, all of these methods use radionuclide salt solutions containing 68Ga, 177Lu, 225Ac, 64Cu, or 211At. No working examples or guidance is provided regarding preparing compounds of claim 10 using other radionuclide salt solutions.
The quantity of experimentation necessary
Experimentation to determine how to use radionuclide salt solutions not containing 68Ga, 177Lu, 225Ac, 64Cu, or 211At to prepare the compounds of claim 10 would be significant. As it is predictable that most radionuclides cannot be used to prepare compounds containing 68Ga, 177Lu, 225Ac, 64Cu, or 211At, it is not clear how a skilled artisan would determine how to successfully perform such reactions.
Because of the known state of the art, and in the absence of experimental evidence and working examples, it is apparent that the amount of experimentation required to determine how to use radionuclide salt solutions not containing 68Ga, 177Lu, 225Ac, 64Cu, or 211At to prepare compounds of claim 10 is very significant and unreasonable due to the known understanding of nuclear chemistry.
Accordingly, the instant claims do not comply with the enablement requirement of §112(a), since to practice the claimed invention in its “full scope,” a person of ordinary skill in the art would have to engage in an unreasonable amount of experimentation, with no reasonable expectation of success. Furthermore, as claim 18 depends from claim 17 and do not resolve the above described enablement issue (this claims also recites “a radionuclide salt solution,” allowing for any radionuclide salt to be used in the scope of the claim), this claim is also rejected.
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 4, 7, 11-13, and 19-22 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.
Claim 4 recites the limitation "the radiolabeled compound of claim 1" in the first clause of the claim. There is insufficient antecedent basis for this limitation in the claim. Claim 1 is drawn to “a precursor compound” while claim 2 is drawn to a radiolabeled compound. As claim 1 does not require or recite a radiolabeled compound, it is not clear to what is being referred by this phrase in claim 4. Therefore the claim is rendered indefinite. As the method of claim 4 produces a molecule of Formula I without a radionuclide being present, for the purpose of examination, the examiner will interpret this to be a method of synthesizing the precursor compound of claim 1. The examiner suggests amending claim 4 to read as “a method of preparing the precursor compound of claim 1…”
Claims 7, 11-13 and 19-22 are drawn to methods of preparing radiolabeled compounds. In each of these claims (and each embodiment within each claim), a mass of a compound represented by Formula I is added to a volume of a buffered solution. However, the way the solution is defined in the current form of the claims is atypical in the chemical arts in a way that results in confusion regarding the meaning of the description. For example, the 68Ga embodiment of claim 7 states that the method involved adding 20-30 µg of the compound represented by Formula I to 0.8-1.4 ml of a sodium acetate solution with a concentration of 0.25M… In this instance, it is not clear what is meant by the phrase “a sodium acetate solution with a concentration of 0.25M.” While one interpretation is that the sodium acetate is present in the solution at the concentration of 0.25M, the current phrasing could also suggest that the compound represented by Formula I is at that concentration. Additionally, the phrasing could imply the presence of another analyte at the provided concentration value and an informality resulted in the loss of the word for the additional analyte. As this phrase could be interpreted multiple ways in each embodiment of each of these methods, resulting in different claim scopes in each instance, these claims are rendered indefinite and are rejected. For the purpose of examination, the examiner will interpret this limitation in each method to mean that the concentration value is associated with the amount of the buffering salt present in each of the solutions, as though the 68Ga embodiment of claim 7 read as “0.8-1.4 ml of a 0.25M sodium acetate solution…”
Allowable Subject Matter
No objection or rejection has been applied to any of claims 1-3, 5-6, 10, and 15-16.
Claims 14, 17, and 18 are rejected under 112(a) for scope of enablement. Accordingly, the examiner concludes that some embodiments of the claimed methods are not enabled. The examiner has not applied art-based rejections to the enabled scopes of these claims and thus considers the enabled embodiments to be allowable.
Claims 4, 7, 11-13, and 19-22 are rejected under 112(b) but would be allowable if rewritten or amended to overcome the rejection set forth in this Office Action.
The examiner has cited prior art below that is relevant to the claimed invention but over which no rejection has been written. The examiner has explained why no rejection has been written over the below-indicated prior art.
Rosch Reference: As relevant prior art, the examiner cites Rosch (US 2017/0327520 A1 – provided by applicant in IDS filed November 15, 2024). The invention of Rosch is drawn to compounds comprising a chelator and a bisphosphonate group (pg. 1, [0001]). Rosch teaches several bisphosphonate groups (pg. 2, [0025]). Rosch teaches several combinations of bisphosphonate group and linkers (pg. 5-8, Table). Rosch also teaches that the chelator attached to these bisphosphonate groups by the linker may be several possible chelator structures, including DOTA (pg. 8-10, [0071]).
Rosch fails to teach compounds that are identical to Formula I of claim 1. While Rosch teaches connecting a bisphosphonate group to a DOTA chelator by a linker, Rosch fails to teach using ibandronate derivatives or linear alkyl linker groups.
Bhushan Reference: As relevant prior art, the examiner cites Bhushan (US 2014/0073780 A1 – provided by applicant in IDS filed November 15, 2024). The invention of Bhushan is drawn to dual-modality bisphosphonate probes containing both a fluorescent moiety and an MRI imaging capable moiety including a chelating group (Abstract and Fig. 5). The compound of Bhushan Figure 5 contains a DOTA chelator connected to a linker via amide bond, an alkyl chain the in the linker, an additional amide bond, a short alkyl region, and then a bisphosphonate group. The fluorophore is attached to a branch off the longer alkyl chain of the linking group. Bhushan teaches coordinating Gd in the DOTA group and using the molecule for MRI (pg. 2, [0013]). Bhushan states that in some embodiments, the bisphosphonate is ibandronate (pg. 2, [0013]).
Bhushan fails to teach specifically using ibandronate as the bisphosphonate group. While Bhushan suggests conjugating ibandronate to a DOTA chelating group, Bhushan does not teach how one would make this linkage. Additionally, Bhushan teaches dual-modality probes containing an additional fluorophore. It is not clear to the examiner in view of the teachings of Bhushan how ibandronate could be used as the bisphosphonate while still including the fluorophore in the compound. Furthermore, Bhushan teaches coordinating lanthanide metals and performing MRI and optical imaging, not radiolabeling the conjugate molecules.
Ogawa Reference: As relevant prior art, the examiner cites Ogawa (Ogawa, K.; et al., Nucl. Med. Biol., 2009 – provided by applicant in IDS filed December 19, 2025). Ogawa teaches the synthesis of DOTA-HBP, a conjugate of DOTA and an amine-terminated bisphosphonate molecule (Scheme 1). Ogawa further teaches radiolabeling DOTA-HBP with 90Y and 177Lu (Section 2.3; and Table 7).
Ogawa fails to teach a conjugate of ibandronate and DOTA and the radiolabeling of such a conjugate. Ogawa differs from the claimed invention in the bisphosphonate group used. While Ogawa uses an amine-terminated bisphosphonate molecule for conjugation to DOTA, Ogawa uses HBP rather than a derivative of ibandronate.
Palma Reference: As relevant prior art, the examiner cites Palma (Palma, E.; et al., Mol BioSyst, 2011 – provided by applicant in IDS filed December 19, 2025). Palma provides a review of bisphosphonate conjugates as radionuclide carriers for imaging and therapeutic use (Abstract). Palma discloses the structure of several known bisphosphonate structures, including ibandronate (Fig. 2). Palma states that ibandronate is 10-fold more potent than pamidronate, an amine-terminated bisphosphonate (pg. 2951, right column, third paragraph). Palma summarizes literature on radioconjugates of bisphosphonates (Table 1) and provides examples of previously taught conjugate structures (Figs. 6-8 and 11).
Palma does not teach an example of an ibandronate derivative being conjugated to DOTA in the way that is required to read on the compound of Formula I of claim 1. While Palma teaches that many different bisphosphonate, linker, and chelator combinations have previously been prepared, there is no teaching of molecules that read on Formula I or examples of bisphosphonate modifications made to link ibandronate to a chelator as required to read on the structure of Formula I in claim 1.
Purely en arguendo, while the skilled artisan in view of the above references may be motivated to combine bisphosphonates such as ibandronate with a chelator like DOTA, none of the above references provide examples of such a conjugate nor suggest particular synthetic means of preparing such a conjugate. Specifically pertaining to claim 1, none of the above cited art, or combinations thereof, teach taking ibandronate, substituting the terminal carbon on the pentyl chain with an amine, and using that amine to form an amide with DOTA to form a conjugate precursor compound for radiolabeling.
For the reasons stated above, no single reference (or potential combinations of multiple references) in the previously cited prior art teaches all the limitations of instant claim 1. This indicates allowable subject matter in claim 1 and thus claims 2-22 due to their relationship or dependence on claim 1 and the incorporation of the compound of Formula I.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric P Mosher whose telephone number is (571)272-3258. The examiner can normally be reached Monday-Friday 9am-5pm.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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