Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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 1-3, 7-9, and 26-35 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. The claims recite a concentration of magnetic nanoparticles from about 0.01 mg Fe/mL to about 100 mg Fe/mL. Applicant has support for 0.01 mg Fe/mL to 100 mg Fe/mL but not for the range reciting “about” since applicant does not contemplate ranges outside of 0.01 mg Fe/mL to 100 mg Fe/mL. It is noted the provisional application and original claims also does not support a range of about 0.01 mg Fe/mL to about 100 mg Fe/mL. The concentrations recited in claims 27-28 also do not have support in the originally filed specification or claims. It is noted that applicant broadly discusses magnetic nanoparticles and concentrations thereof but does not discuss Fe/mL specifically and effective concentrations; thus one cannot state this is inherent support. The recitation that the nanoparticles are in an effective concentration in terms of Fe/ml was not contemplated in the originally filed specification. Further, ‘about’ 1kA/m does not have support (note about 100 kA/m does have support). The specification teaches “at least 1 kA/m” but not contemplate ranges lower than “1kA/m.”
Claim 29 recites at least 10 watts/gram Fe does not have support in the originally filed specification or claims. Claim 35 recites the absorption rate (at least 0.1 W/ml) do not have support in the originally filed specification or claims.
If applicant contends there is support, applicant is requested to point out the specific page and line of said support.
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 1-3, 7-9, and 26-35 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 1 has been amended to recite: A cryoprotective composition for a biospecimen comprising…” The body of the claim only recites “a cryoprotective agent” and “magnetic nanoparticles.” However, the wherein clause states the cryoprotective composition is in a cryopreserved state in a cryopreserved biospecimen.
It appears applicant is attempting to claim a composition comprising “a cryoprotective agent”; “magnetic nanoparticles”; and a biospecimen. However, the use of the phrase a “in a cryopreserved biospecimen” cause a lack of clarity of what specifically the composition comprises and what is being claimed. Is a composition or cryopreserved biospecimen being claimed. The preamble states the that composition is for a biospecimen but the body of the claim does not comprise the biospecimen. The wherein clause attempts to limit the claim but recites a ‘cryopreserved biospecimen.’ It is unclear if the biospecimen is in a cryopreserved state prior to interaction with the cryoprotective composition. The use of a “cryopreserved biospecimen” in the independent claim and dependent claims causes a lack of clarity in the claim. The dependent claims refer to just the “cryopreserved biospecimen” and at times “cryoprotective composition” as if they are two different products. For instance, claim 2 limits the concentration and effects of the nanoparticles to the ‘cryopreserved biospecimen” but claim 32 for instance limits the effects on the cryoprotecting composition.
It is suggested the applicant use consistent terminology in the independent claim and dependent claims. It is suggested the claim is amended to recite “biospecimen” in the body of the claim and not just in the wherein clause and amend the wherein clause to “the cryoprotective composition comprising the biospecimen is in a cryopreserved state.” The claim will be interpreted in such a manner that is consistent with the specification. It is noted that applicant does not teach cryopreserving a biospecimen prior to contacting it with the claimed cryoprotective composition. However, a 112a is not being made at this time since it appears to be more of typographical and grammatical errors.
The second wherein clause “wherein the nanoparticle distribution is effective for magnetically induced rewarming throughout a cryopreserved specimen in the cryopreserved biospecimen with reduced ice crystallization and/or thermal stress compared to rewarming by boundary heating or microwave heating. It is unclear if “a cryopreserved specimen” is referring to the cryopreserved biospecimen of lines 10-11 and the phrase throughout a cryopreserved specimen in the cryopreserved biospecimen lacks clarity. It is suggested the applicant use consistent terminology throughout the claim.
Claim 21 recites the rewarming and thermal stress is independent of the size the cryoprotective composition which is unclear how the composition itself has a size since the composition itself is not a solid.
Claim Objection
It is suggested that all the claims are amended to a consistent preamble. The claims at times recite “the composition” and at times recite “the cryoprotective composition.”
Claim Rejections - 35 U.S.C. § 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.
Claims 1-3, 7-9, and 26-35 remain rejected under 35 U.S.C. § 103(a) as being unpatentable over Gabbai (WO 2007/077560; 2007; cited in the IDS filed 5/17/2017) in view of Bordelon et al. (Journal of Applied Physics, Vol. 109, No 124904, pp. 1-8; 2011) or vice-versa as upheld by the Board Decision of 9/2/2025 in view of Deng et al ("Rapid electromagnetic rewarming of cryopreserved tissues using nano- magnetoparticlesfeasibility study", 427-428 cited in the IDS of 5/17/20174 ) in view of Etheridge et al (Optimizing Magnetic Nanoparticle Based Thermal Therapies Within the Physical Limits of Heating-published online 8/2/2012-cited in IDS 5/17/2017).
Regarding claim 1, Gabbai teaches cryoprotective compositions comprising a biospecimen (see page 19) including cells, organs, (reads on at least 0.1mm) and tissues and methods of using them to preserve biological material, where the composition is contacted with the cellular matter. The composition includes a cryoprotective agent, including a starch or dextran, and a nanostructure, wherein the core material of the nanostructure may comprise ferromagnetic (page 4, lines 16-18 and page 5, lines 26-29; specifically, page 5, lines 4-6; and 27-29). The core may have a crystalline structure. See page 13. Gabbai teaches this cryoprotective composition comprising nanostructures and a cryoprotective agent reduces the injury of cells caused by intracellular and extracellular ice crystal formation during freezing and thawing (page 11, lines 12-29). Gabbai teaches Gabbai teaches use of electromagnetic radiation for the thawing and recovery of the material. Gabbai teaches as thawing occurs ice crystals form and increase in size; thus rapid reheating should be done. Gabbai teaches using their cryoprotective composition in a cryopreserved state (pages 19-20). The cryoprotecting agents or nanostructures in the composition may be at a high enough concentration, such that contacting triggers vitrification of the cellular matter. A preferred concentration of nanostructures is below 1020 nanostructures per liter and more preferably below 1015 nanostructures per liter. Regarding claim 3, Gabbai teaches concentrations of cryoprotecting agents may range from about 4 M to about 10 M (page 24, lines 10-15). Gabbai is teaches that both starch and dextran are cryoprotective agents (see page 6, lines 11-22).
Gabbai does not teach the instantly claimed magnetic nanoparticles.
Bordelon teaches magnetic nanoparticles for heating when using magnetic fields. Bordelon teaches magnetic particles for biomedical applications including cancer hyperthermia therapy. Bordelon teaches the magnetic/structural properties of the particles largely determine the heating efficiency of particular AMF conditions. Bordelon teaches heating the nanoparticles using instantly claimed radiation. Bordelon teaches two aqueous ferromagnetic nanoparticles (MNP) formulations:
1) BNF-Starch particles having a diameter of 100 nm core/shell and iron oxide a diameter of 15-20nm, in solution with starch at a concentration of 29.1 mg Fe/mL, and
2) nanomag®-D-spio having a colloidal diameter of 100 nm and iron oxide a diameter of 10-12nm, in solution with dextran at a concentration of 6 mg Fe/mL, both commercially available from Micromod Partikeltechnologie (see page 2, column 2, paragraph 3; Table I).
Bordelon teaches the nanoparticles generate heat upon excitation by a RF field with a magnetic field strength between about 1kA/m and about 100 kA/m (see Figure 3). Bordelon teaches the testing of the magnetic nanoparticles to generate uniform fields of heating at 100kA/m. see abstract. The reference teaches the need for homogenous distribution in the tissues and organs and use of the appropriate AMF to prevent over heating. see page 109, second column. Bordelon teaches diameters of 100 nm, Bordelon shows in Figure 1 that several nanoparticles in each sample had diameters less than 100 nm, and less than 80 nm (see Figure 1). Note Gabbai is teaches that both starch and dextran are inherently cryoprotective agents (see page 6, lines 11-22). *It is noted that Bordelon teaches the properties of the particle itself and the AMF range effect the heating of the tissue.
Deng teaches cryopreservation using nano-particles. Deng teaches both cooling and rewarming are critical to the survival of the cells/tissues/organs. Deng teaches that cooling may cause ice crystals and rapid rewarming is critical for survival of cryopreserved tissues especially done via vitrification to avoid ice crystallization. Deng teaches the use of nanoparticles to perform rapid and uniform electromagnetic (heating is generate volumetrically) rewarming of cryopreserved tissue which is better than conventional methods. Deng compares rewarming using nanoparticles and without and notes electromagnetic rewarming is uniform using the nanoparticles. Further Deng teaches for large pieces of samples (more than a few millimeters) the use of nanoparticles is needed. Deng teaches the principle of rewarming is similar to electromagnetic induced nano-hyperthermia. See page 427.
Etheridge teaches nanoparticles have been used in cancer hyperthermia.. Etheridge teaches although mNPs can retain dispersion in aqueous solution, aggregation is common in biological systems, due to protein interactions and sequestering in vesicles during cellular uptake. Tightly aggregated mNPs will affect the magnetic response of neighboring particles, due to overlapping local magnetizations. These interactions have been shown to both augment and interfere with mNP heating.
Nanoparticle size have been shown to have effect on biodistribution and cellular uptake. Smaller particles permeate the tissue more easily and can readily be washed out. Etheridge teaches that many factors will have effects on nanoparticles physiological interactions including the size for thermal performance. The reference further teaches that besides mNP concentration, the field intensity also is a key perimeter. It was estimated that optimal heating for both mNPs will be achieved at fields of approximately 100 kHz and ‡20 kA/m. Etheridge teaches nanoparticles composed of 60-80nm (20nm crystallites) with a starch coating (Micromod fmNP) the same commercial available ferromagnetic particle as taught by Bordelon.
It would have been obvious to combine Bordelon and Gabbai and utilize Bordelon’s nanoparticles in Gabbai’s composition or use Bordelon’s composition as a cryopreserving composition for cryopreserving a specimen. One would have been motivated to utilize Bordelon’s nanoparticles in Gabbai’s composition since Deng teaches that the reheating of cryopreserved material functions on the same principle as hyperthermia therapy. Thus, although Bordelon’s composition is taught for cancer hyperthermia therapy, Bordelon’s teaches commercially available magnetic nanoparticles comprising cryopreservatives and the use electromagnetic radiation to heat and provide uniform heating. Furthermore, Gabbai stresses the importance of rapid rewarming to avoid ice crystals and Deng and Bordelon teach the magnetic nanoparticles used in cancer hyperthermia therapy have the ability to rapidly and uniformly reheat. Thus, one would reasonably expect success employing Bordelon’s nanostructures in Gabbai’s cryopreserved composition and have the advantage of providing rapid and uniform rewarming of the specimen as required by Gabbai.
Regarding the wherein clause, since the combination Gabbai and Bordelon teach the same structure, i.e. a “a cryoprotective agent” and magnetic nanoparticles that are defined as superparamagnetic nanoparticles comprising iron and having a core diameter of no more than 20 nm; or ferromagnetic nanoparticles having a core diameter of no more than 100 nm; in a concentration from about 0.1 mg Fe/mL to about 100 mg Fe/mL; and a biospecimen, the composition would inherently function as claimed when electromagnetic field is applied. It is also noted that Deng teaches the properties claimed such as reducing ice crystallization and uniform distribution and rapid rewarming using the magnetic nanoparticles. Etheridge further substantiate this position. Etheridge states nanoparticle size has an effect on biodistribution and cellular uptake and smaller particles permeate the tissue more easily. Thus, since Bordelon teaches the same size as claimed and the same magnetic field strength as claimed, the functional limitation of uniform distribution would be implicit from the combination. Thus, the argued distribution of the particles in the specimen would have to be the same absent evidence to the contrary. It is noted that the specification also discusses the nanoparticles size provides the “effective distribution” and the use of a certain range of the electromagnetic field.
Regarding the SARFe and SARv in claims 29 and 35, it is initially noted that the originally filed specification indicates measuring mass-normalized, field dependent heating (SARFe) of commercially available Micromod (ferromagnetic; 60-80 nm core) magnetic nanoparticles (mNPs) in dispersed, aqueous solution at room temperature (page 3, lines 10-12, page 13, line 1; Fig. 5b). Additionally, the originally filed specification indicates that volumetric heating (SARV) demonstrates a direct dependence on mNP concentration (page 3, lines 14-15; Fig. 5d). It is additionally noted that in the originally filed specification, the SARV can be normalized to the nanoparticle mass (SARFe, W/mg Fe) (SARV = SARFe × [mNP]; page 12, lines 21-22).
Regarding the SARFe and SARv in claims 29 and 35, Bordelon also teaches characterization of the heat produced, (i.e., SPL), over a wide AMF amplitude range of the composition of BNF-Starch particles and the nanomag®-D-spio, (page 2, column 2, paragraph 3; Table I). Bordelon characterization of amplitude-dependent SPL of the dextran-iron oxide nanoparticle suspensions was performed through saturation to 94 kA/m with a uniform field to 100 kA/m at ~150 kHz (Abstract). Bordelon determining the appropriate range of the heating curve from which the SPL, and that these results agree with SPL values calculated from the phenomenological Box-Lucas equation (Abstract). Amplitude-dependent SPL results are shown in Fig. 5, and Table II provides a summary of select values (page 4, column 1, paragraph 2; Table II). Bordelon teaches that the Micromod BNF-Starch particles display relatively poor heating at low amplitude with rapidly increasing heating efficiency between 24 and 64 kA/m, and a maximum SPL of 537±8 W/g Fe (i.e., 0.537 ±8 W/mg Fe) above 80 kA/m (page 4, column 1, paragraph 2; Table II). By contrast the Micromod nanomag®-D-spio particles produce heat more efficiently at low field than the BNF-Starch particles to ~24 kA/m (page 4, column 1, paragraph 2; Table II). The nanomag®-D-spio related SPL then plateaus at ~30 kA/m and reaches only 162 ±3 W/g Fe (i.e., 0.162 ±3 W/mg Fe) at 94 kA/m (page 5, column 1, paragraph 2; Table II).
Regarding the SARFe and SARv in claims 29 and 35, in view of the above, Bordelon is utilizing the same type of commercially available Micromod mNPs as Applicant, where the Bordelon is characterizing mNPs utilizing field strengths (i.e., 0-100 kA/m) and W/g Fe within the claimed ranges as Applicant (i.e., Bordelon teaches normalized compositions greater than 10 W/g Fe). If according to the originally filed specification that the SARV can be normalized to the nanoparticle mass (SARFe, W/mg Fe) (SARV = SARFe × [mNP]; page 12, lines 21-22), then Bordelon teaches, utilizing the same type of commercially available mNPs as Applicant where the BNF-Starch and nanomag®-D-spio particles would have a SARv of 15.6 W/ml (i.e., 0.537 ±8 W/mg Fe × 29.1 mg/ml) and 0.97 W/ml (i.e., 0.162 ±3 W/mg Fe × 6 mg/ml), respectively.
Secondly, a skilled artisan would have been motivated to add a biospecimen to Bordelon’s composition and use it for cryopreservation since Bordelon’s composition comprises known cryoprotects along with nanoparticles and Gabbai establishes that start/dextran (cryoprotective agents) in combination with ferromagnetic particles act as cryopreserving composition for biospecimens. Thus, the addition of a biospecimen to Bordelon’s composition to cryopreserve it would be an obvious use in light of the art cited. Deng also establishes that nanoparticles used for nano-hyperthermia therapy and rewarming cryopreserved material, function on the same principle of using electromagnetic heating to heat nanoparticles in a uniform and rapid manner. Thus, a person of ordinary skill in the art would have had a reasonable expectation of success in using Bordelon’s composition as a cryopreserving composition in a cryopreserved state with a biospecimen for the reasons discussed above (the principle of rewarming function similarly to hyperthermia therapy). The functional limitations would be inherent since Bordelon teaches the same cryopreserving components which would act in the same manner when a biospecimen is added. Etheridge establish the particle size effects particle distribution in tissues.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Response to Arguments
The Board Decision of 9/2/2025 affirming Bordelon et al in view of Gabbai et al is noted and incorporated herein. The new rejection cited above address applicant’s amendment incorporating a biospecimen and the argued functional limitations.
Pertinent Prior Art
Kim et al. New Eng. J. Med 2010;363(25):2434-2443, 2010 is cited teaching superparamagnetic iron oxide nanoparticles (SPIONs) including dextran-coated SPIONs. Kim observes that smaller sized nanoparticles are easily taken up by the tissue and the dextran coat increased the circulation time of the nanoparticles.
Conclusion
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/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653
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