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 .
Acknowledgement of Receipt
Applicant’s Response, filed 3/19/2026, in reply to the Office Action mailed 11/20/2025, is acknowledged and has been entered. Claims 131-172 are pending and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. The previous rejection has been modified in view of claim amendment. The Examiner’s response to Applicant’s arguments are incorporated below. New grounds for rejection are set forth herein, necessitated by claim amendment.
Claim Rejections - 35 USC § 112
Claims 155-158 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 131, from which claim 155 depends, states “administering to a subject a composition comprising multi-armed polyethylene glycol (PEG) nanoconstructs, wherein the nanoconstructs are essentially free from other MRI imaging and/or contrast agents, including from any heavy metal or isotopic agents. However, claim 155 recites wherein the nanoconstructs comprise one or more optical agents. As an optical agent is a contrast agent, the language in claim 131 is confusing because it is unclear if only MRI imaging agents and MRI contrast agents are intended to be excluded, or all other contrast agents.
The dependent claims fall therewith.
Clarification is requested.
Claim Rejections - 35 USC § 103
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.
Claim(s) 131-150 and 153-172 are rejected under 35 U.S.C. 103 as being unpatentable over Kalifa et al (US 2015/0328315) in view of Alvares et al. (Mag. Res. Med., 2017, 77, p. 1553–1561).
The instant claims are directed to a method for obtaining magnetic resonance imaging (MRI) images in a target tissue within a subject, the method comprising: (a) administering to a subject a composition comprising multi-armed polyethylene glycol (PEG) nanoconstructs, wherein the nanoconstructs are essentially free from other MRI imaging and/or contrast agents, including from any heavy metal or isotopic agents, and wherein the nanoconstructs comprise more than two arms; (b) after a period of time sufficient for nanoconstructs of the composition to accumulate in a target tissue if one is present in the subject, exposing the subject to an MRI imaging protocol; and (c) detecting nanoconstruct signals, in response to the MRI imaging protocol, to obtain MRI images, wherein the MRI images comprise a graphical representation of the target tissue within the subject, wherein the nanoconstruct signals comprise multi-armed PEG signals, and wherein the multi-armed PEG signals comprise PEG proton signals. In claims 169 step b includes exposing the subject to an MRI imaging protocol, wherein the MRI imaging protocol comprises parameters to generate a diffusion b value greater than 108 s/m2. Claim 170 further includes step (d), applying a filtering protocol to sufficiently suppress signals from water and/or fat within the subject, produced in response to the MRI imaging protocol, as compared to the nanoconstruct signals to selectively detect the nanoconstruct signals.
Kalifa teaches treating (e.g., ablating) cardiac tissue, comprising: a) contacting an animal with a nanoparticle comprising a matrix, a toxic (e.g., ablative) agent (e.g., sonosensitizer, chemotherapeutic agent (e.g., doxorubicin or cisplatin), or photosensitizer), and a cardiac targeting moiety; and b) administering an activator of the toxic agent (e.g., light, chemical (e.g., pharmaceutical agent) or ultrasound) to at least a portion of the cardiac tissue (e.g., heart) of the animal to activate the toxic agent. In some embodiments, administering the activator kills (e.g., ablates) cardiac tissue only where activator is administered and only to targeted cells. In some embodiments, the cardiac targeting moiety is a cardiac targeting peptide (e.g., SEQ ID NO:1). In some embodiments, the photosensitizer is methylene blue, Photofrin, 2-devinyl-2-(1-hexyloxyethyl)pyropheophorbide (HPPH), chlorin e6 (Ce6), coomassie blue, or gold. In some embodiments, the contacting is via intravenous administration. In some embodiments, the cardiac targeting moiety specifically targets cardiac myocytes. In some embodiments, the nanoparticle is a PEG molecule (e.g., 8-arm PEG). In some embodiments, the nanoparticle is approximately 10 nm or less in size (paragraph 0008).
In some embodiments, the method further comprises the step of imaging the nanoparticles in the animal. In some embodiments, the imaging is performed after the administering of activator and optionally determines a treatment course of action (e.g., further administering of activator, location of treatment and/or nanoparticles). In some embodiments, the nanoparticles further comprise an imaging contrast agent (e.g., gold, iron oxide, iodine, etc.) or are designed to have imagable properties themselves. In some embodiments, the method further comprises the step of visualizing the imaging agent in the animal (e.g., via X-ray imaging, PET, photacoustic imaging, ultrasound, computer tomography (CT) imaging, or magnetic resonance imaging (MRI)). (paragraph 0010, claim 17).
In Example 3, CTP-Ce6-8-arm PEG was prepared. Adult male rats were sedated and a tail vein injection with -CTP-Ce6/Rh-8-arm PEG. 10 kDa PEG is taught (paragraph 0126).
Sonodynamic therapy is based on the synergistic effect of ultrasound and a chemical compound referred to as “sonosensitizer”. The effect can be localized by focusing the ultrasound on a defined region (e.g., regions of cardiac tissue). In some embodiments, ultrasound is delivered transdermally to a specific region of cardiac tissue. In some embodiments, activators are pharmaceutical agents that activate therapeutic agents (e.g., chemotherapeutic agents). For example, in some embodiments, verapamil is used to active or improve efficacy of chemotherapeutic agents (e.g., doxorubicin) (paragraph 0071-2).
Kalifa does not specifically exemplify perform nuclear magnetic resonance image of the multi-armed PEG in the plurality of nanoconstructs.
Alvares teaches that 1H MRI is an established diagnostic method that generally relies on detection of water. Imaging specific macro-molecules is normally accomplished only indirectly through the use of paramagnetic tags, which alter the water signal in their vicinity. We demonstrate a new approach in which macromolecular constituents, such as proteins and drug delivery systems, are observed directly and quantitatively in vivo using 1 HMRI of 13C-labeled poly(ethylene glycol) (13 C-PEG) tags. Methods: Molecular imaging of 13 C-PEG-labeled species was accomplished by incorporating a modified heteronuclear multiple quantum coherence filter into a gradient echo imaging sequence. We demonstrate the approach by monitoring the real-time distribution of 13 C-PEG and 13 C-PEGylated albumin injected into the hind leg of a mouse. Results: Filtering the 1 H PEG signal through the directly coupled 13 C nuclei largely eliminates background water and fat signals, thus enabling the imaging of molecules using 1 HMRI. In conclusion, PEGylation is widely employed to enhance the performance of a multitude of macromolecular therapeutics and drug delivery systems, and 13 C-filtered 1H MRI of 13C-PEG thus offers the possibility of imaging and quantitating their distribution in living systems in real time (page 1553).
Anatomical images were acquired with a standard fast spin echo (RARE) sequence (5 s TR, 14 ms TE,RARE factor of 8, 256 acquisition matrix) (page 1555).
In vivo imaging is taught on page 1555. A healthy 30 g adult male BALB/cJ mouse (The Jackson Laboratory, Bar Harbor, ME) was anesthetized and prepared, as previously described. The lower thigh of the left hind limb was injected intramuscularly with the 13C-PEG-BSA conjugate (2.4 mM; 50 µL; 122 nmol; 4.1 nmol/g of mouse; saline). Filtered, blanking, and anatomical images were acquired under similar conditions to the in vivo injection of the polymer. After a second injection of the conjugate, the concentration was quantified using a 5-mm NMR tube of 13C-PEG in 30% poly(acrylamide) gel as an external concentration standard.
Diffusion NMR results, obtained as noted in the NMR Methods sub-section, indicated a conjugate diffusion coefficient of
2.62
×
1
0
-
11
m2/s (Figure S3). Assuming that 13C PEG-BSA tumbles isotropically, using the Stokes-Einstein equation,(5) this translates to a hydrodynamic diameter of 15.2 nm which is roughly 2 fold larger than observed for BSA (7.8 nm).
Diffusion NMR results, obtained as noted in the NMR Methods sub-section, indicated a conjugate diffusion coefficient of
2.62
×
1
0
-
11
m2/s (Figure S3). Assuming that 13C PEG-BSA tumbles isotropically, using the Stokes-Einstein equation,(5) this translates to a hydrodynamic diameter of 15.2 nm which is roughly 2 fold larger than observed for BSA (7.8 nm).
It would have been obvious to one of ordinary skill in the art at the time of the invention to perform MRI imaging after administering CTP-Ce6-8-arm PEG nanoparticles to an animal. One would have been motivated to do so because Kalifa teaches that the nanoparticles may be designed to carry an imaging agent or may have imagable properties themselves, and the method further comprises the step of visualizing the imaging agent in the animal, including via MRI. One would have had a reasonable expectation of success in doing so because Alvares teaches that macromolecular constituents, such as proteins and drug delivery systems, are observed directly and quantitatively in vivo using 1H MRI of 13C-labeled poly(ethylene glycol) (13C-PEG) tags.
Regarding claim 135, while Kalifa does not specifically recite the number of protons, however the 8-arm PEG comprises the same molecular weight and nanoparticle size as required by the instant claims, see claims 132-134. Accordingly, the 8-arm PEG would necessarily be capable of carrying the same number of protons.
Regarding claim 138, Alvares teaches MRI or PEG or PEG-protein conjugate. One of ordinary skill in the art could have substituted a multiarm PEG as taught by Alvares as functionally equivalent. Regarding claim 136 directed to lifetime of activity and 139 directed to T2, a composition and its properties are inseparable. “Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure or composition as that which is claimed, the properties applicant discloses and/or claims are necessarily present. See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The “discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” See Atlas Power Co. v. Ireco Inc., 51 USPQ 2d 1943, 1947 (Fed. Cir. 1999). Therefore, merely claiming a new use, new function, or new property, which is inherently present in the prior art does not make the claim patentable. See In re Best, 195 USPQ 430, 433 (CCPA 1977), and MPEP § 2112.
With regard to the amended claim language comprising multi-armed polyethylene glycol (PEG) nanoconstructs, wherein the nanoconstructs are essentially free from other MRI imaging and/or contrast agents, including from any heavy metal or isotopic agents, it is noted that 13C present in Alvares is not employed as a contrast agent, since 1H imaging is performed in the reference, as in the instant claims. See also MPEP 2111.03. For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, “consisting essentially of” will be construed as equivalent to “comprising.” See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355 (“PPG could have defined the scope of the phrase ‘consisting essentially of’ for purposes of its patent by making clear in its specification what it regarded as constituting a material change in the basic and novel characteristics of the invention.”). See also AK Steel Corp. v. Sollac, 344 F.3d 1234, 1240-41, 68 USPQ2d 1280, 1283-84 (Fed. Cir. 2003). Also, claim 169 does not recite the language wherein the nanoconstructs are essentially free from other MRI imaging and/or contrast agents.
With regard to diffusion coefficient in claim 169, administration of 8-arm PEG as taught by Kalifa, and MRI imaging is taught by Kalifa/Alvares, it is considered that the diffusion coefficient would be an inherent property of administration and performing MR imaging. A composition and it’s properties are inseparable. “Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure or composition as that which is claimed, the properties applicant discloses and/or claims are necessarily present. See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The “discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” See Atlas Power Co. v. Ireco Inc., 51 USPQ 2d 1943, 1947 (Fed. Cir. 1999). Therefore, merely claiming a new use, new function, or new property, which is inherently present in the prior art does not make the claim patentable. See In re Best, 195 USPQ 430, 433 (CCPA 1977), and MPEP § 2112.
Claim(s) 131-172 are rejected under 35 U.S.C. 103 as being unpatentable over Kalifa et al (US 2015/0328315) in view of Alvares et al. (Mag. Res. Med., 2017, 77, p. 1553–1561), in further view of Bradbury et al. (US 2014/0248210).
The rejection over Kalifa in view of Alvares is applied as above.
With regard to claims 151 and 152, Kalifa and Alvares do not teach RGD as a targeting ligand.
Bradbury teaches silica-based nanoparticle that allows for precise detection, characterization, monitoring and treatment of a disease such as cancer…To facilitate efficient urinary excretion of the nanoparticle, it may be coated with an organic polymer, such as poly(ethylene glycol) (PEG). The small size of the nanoparticle, the silica base and the organic polymer coating minimizes the toxicity of the nanoparticle when administered in vivo. In order to target a specific cell type, the nanoparticle may further be conjugated to a ligand, which is capable of binding to a cellular component associated with the specific cell type, such as a tumor marker.
The ligand may be capable of binding to at least one cellular component, such as a tumor marker. The number of ligands attached to the nanoparticle may also range from about 1 to about 30, from about 1 to about 25, or from about 1 to about 10. Examples of the ligand include peptide, protein, biopolymer, synthetic polymer, antigen, antibody, microorganism, virus, receptor, hapten, enzyme, hormone, chemical compound, pathogen, toxin, surface modifier, or combinations thereof. Peptides such as tripeptide RGD, cyclic peptide cRGD, cyclic peptide cRGDYC, octreotate, EPPT1 and peptide analogs of alpha-MSH are encompassed by the present invention. Any linear, cyclic or branched peptide containing the RGD or alpha-MSH sequence is within the scope of the present invention (paragraph 0013).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide RGD as a targeting ligand in the methods for MR imaging PEG nanoparticles taught by Kalifa in view of Alvares when the teachings of Kalifa and Alvares are taken in view of Bradbury. One would have been motivated to do so, with a reasonable expectation of success, because Kalifa teaches that the nanoparticles may contain a targeting ligand, and Bradbury teaches RGD to be a suitable targeting ligand for conjugation to a PEG containing nanoparticle for characterization, monitoring and treatment of a disease such as cancer.
Response to arguments
Applicant argues that Alvares teaches away from MRI imaging of CTP-Ce6-8-arm PEG nanoparticles of Kalifa. Applicant asserts that Alvares discloses challenges in direct MRI imaging of specific molecules as their signals would be overwhelmed by water. See Alvares at p. 1553. To overcome these challenges, Alvares modifies PEG molecules with ¹³C isotopes that produce distinct MRI signals that can be distinguished from water MRI signals. See Alvares at Fig. A1. Absent ¹³C isotopes, MRI signals from MRI molecules in Alvares would be overwhelmed by water. Id. Therefore, a person of ordinary skill in the art reading Alvares would not have had a reasonable expectation of success of performing MRI imaging on PEG molecules without ¹³C isotopes.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that Alvares performes 13 C-filtered 1H MRI of 13C-PEG, as such it is considered that 13C itself is not an imaging agent which is potentially excluded by the instant claims. See also MPEP 2111.03. For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, “consisting essentially of” will be construed as equivalent to “comprising.” See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355 (“PPG could have defined the scope of the phrase ‘consisting essentially of’ for purposes of its patent by making clear in its specification what it regarded as constituting a material change in the basic and novel characteristics of the invention.”). See also AK Steel Corp. v. Sollac, 344 F.3d 1234, 1240-41, 68 USPQ2d 1280, 1283-84 (Fed. Cir. 2003). Also, claim 169 does not recite the language wherein the nanoconstructs are essentially free from other MRI imaging and/or contrast agents. The language “essentially free” is interpreted in a similar manner. Applicant’s arguments have been fully considered but is respectfully considered that the Alvares reference does not rise to the level of teaching away from the instant claims.
Applicant further argues that a person of ordinary skill in the art reading Kalifa as a whole would have understood that MRI imaging or contrast agents are needed to perform MRI imaging of the nanoparticles. Furthermore, Kalifa discloses a laundry list of imaging modalities: X-ray imaging, PET, photoacoustic imaging, ultrasound, computer tomography (CT) imaging, or magnetic resonance imaging (MRI)). Id. Applicant asserts that a person of ordinary skill in the art reading Kalifa at para. [0010] would not have understood that any of Kalifa's nanoparticles may be imaged using any of the disclosed modalities, but rather would have recognized that some nanoparticles may be imaged by themselves in certain imaging modalities, but for other imaging modalities the nanoparticles need appropriate imaging agents.
Applicant’s arguments have been fully considered but are not persuasive. It is respectfully submitted that Kalifa readily teaches that the PEG nanoparticles further comprise an imaging contrast agent (e.g., gold, iron oxide, iodine, etc.) or are designed to have imagable properties themselves, including via MRI. See MPEP 2123. Patents are relevant as prior art for all they contain. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998). Accordingly, one of ordinary skill in the art could have readily selected from among the suitable imaging modalities.
Applicant argues that Kalifa is silent about any MRI imaging protocols, let alone for imaging CTP-Ce6-8-arm PEG nanoparticles, whereas Alvares explains that MRI signals from such nanoparticles would be overwhelmed by that of water. In contrast, the present Specification outlines specific MRI protocols for imaging of PEG nanoconstructs to overcome abundant water signals. Applicant further argues that regarding claims 143 and 169, the references do not recite a diffusion b value greater than 10⁸ s/m2.
Applicant’s arguments have been fully considered but are not found to be persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case it is respectfully submitted that Alvares readily teaches MRI imaging protocol for PEG. With regard to diffusion coefficient, administration of 8-arm PEG as taught by Kalifa, and MRI imaging is taught by Kalifa/Alvares, it is considered that the diffusion coefficient would be an inherent property of administration and performing MR imaging. A composition and it’s properties are inseparable.
“Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure or composition as that which is claimed, the properties applicant discloses and/or claims are necessarily present. See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The “discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” See Atlas Power Co. v. Ireco Inc., 51 USPQ 2d 1943, 1947 (Fed. Cir. 1999). Therefore, merely claiming a new use, new function, or new property, which is inherently present in the prior art does not make the claim patentable. See In re Best, 195 USPQ 430, 433 (CCPA 1977), and MPEP § 2112. Applicant’s arguments have been fully considered but the rejections are maintained.
Conclusion
No claims are allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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