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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-22 and 36 and the species where the metal is a transition metal with an oxidation state of +2, the polymer is a polyalkylene glycol or polyalkylene oxide, and Lig and Lig’ are formed from 3,5-di(pyridine-4-yl)phenyl)methanol in the reply filed on August 24, 2026 is acknowledged. Claims 22-35 and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Objections
Claims 1, 5, 13, and 18 are objected to because of the following informalities:
In line 4 of claim 1, “+4, +4” is redundant and should read “+4.”
In line 2 of claim 5, the limitation “the frozen composition flash-frozen” should include a verb. One way to correct this is to replace this limitation with “the frozen composition is prepared by flash-freezing.”
In line 15 of claim 13, the examiner suggests replacing the “at least 1, in” with “at least 1 in” for the utmost clarity that that proviso that ab + bb is at least 1 is only required for one of P1, M, and P2.
In line 17 of claim 13, “a group 15 metal, a transition metal” should read “a group 15 metal, or a transition metal.”
In line 20 of claim 13, “+4, +4” is redundant and should read “+4.”
In line 10 of claim 18, “poly(methacrylic acid), poly(hydroxyethyl acrylate)” should read “poly(methacrylic acid), or poly(hydroxyethyl acrylate).”
In line 12 of claim 18, “a acrylamide” should read “an acrylamide.”
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.
Claims 1-22 and 36 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 recites the limitation "the sample" in line 2. There is insufficient antecedent basis for this limitation in the claim. This can be corrected by replacing “the sample” with “a sample.”
Claims 2-22 and 36 are rejected along with claim 1 because they depend from claim 1 and require all the limitations of claim 1, including those that are indefinite.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4, 11-21, and 36 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Johnson (US 2015/0225438 A1, cited with 6/23/2024 Office action).
Regarding claims 1-4, 11-12, and 18-20, Johnson discloses supramolecular complexes that include nanostructures formed through metal-ligand coordination and junction self-assembly ([0199]). Johnson further discloses a cryo-TEM image of a supramolecular complex (Figure 19A). These samples are produced from Pd2+ and a polymer referred to as “B-3” that has the structure shown below and are dialyzed against water (Figure 16C, [0459], [0184]).
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Johnson’s supramolecular complexes read on metallo-supramolecular branched polymers (MSBP). Cryo-TEM of aqueous samples necessarily requires freezing. Johnson therefore discloses a method of imaging a sample comprising imaging a frozen composition of a MSBP with a metal oxidation state of +2 where a portion of the MSBP reads on the claimed sample and a portion of the MSBP reads on the claimed MSBP (claim 1). Freezing an aqueous composition results in a composition comprising ice (claim 4). The MSBP is dialyzed against water, indicating that the MSBP is hydrophilic (claim 2). The MSBP comprises a segment derived from polyethylene glycol (claims 18 and 20), reading on a neutral hydrophilic polymer segment (claims 12 and 19) ([0354]). The Pd2+ ions are positively charged, leading to a MSBP with a slight positive charge (claim 3) ([0283]). In addition, the metal binds with the chelating group of “B-3” (see Figure 16B), reading on the metal is bonded to components of the MSBP via dative bonds (claim 11) (see page 5, lines 25-27 of the instant specification).
Regarding claims 13-17 and 36, Johnson discloses the method of claim 1. Johnson describes the cryo-TEM image as including aggregates of M12L24 spheres dialyzed against water ([0184] and Figure 19A).
Figure I-1 of Figure 1B is shown below because it provides a schematic of a M12L24 cage. The spheres represent metal ions ([0268]).
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Johnson’s MSBP comprises a structure of Formula I (claim 13). In particular, the M12L24 cage comprise 3 adjacent structural units reading on Formula II where M’ is a metal with an oxidation state of +2 (Pd2+); Q1’, P1’, P2’, and Q2’ are Lig-polymer segment-Lig’ (portion derived from “B-3”); and yb, ab, bb, xb, and zb are 1. These 3 structures of Formula II read on P1, M, and P2 in Formula I where P1, M, and P2 are 1. In addition, the M12L24 cage comprises a
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structure because the P1, M, and P2 structures are adjacent. “B-3” has two chain end groups (corresponding to instant Lig and Lig’) that are 3,5-di(pyridin-4-yl)phenyl)methyl groups (claims 14-17). Pd2+ is a group 10 metal with an oxidation state of +2 (claim 36).
Regarding claim 21, Johnson discloses the method of claim 1. Johnson further prepares the MSBP by exposure of “B-3” to Pd(NO3)·2H2O ([0455]). This reads on wherein the MSBP is formed by reacting
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with a salt of the metal.
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.
Claims 4-10 and 22, are rejected under 35 U.S.C. 103 as being unpatentable over Johnson (US 2015/0225438 A1, cited with 6/23/2024 Office action) as applied to claim 1 above, and further in view of Stewart (Cryo-electron microscopy and cryo-electron tomography of nanoparticles, Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 2017, 9:e1417) and Kuntsche (Cryogenic transmission electron microscopy (cryo-TEM) for studying the morphology of colloidal drug delivery systems, International Journal of Pharmaceutics, 2011, 417, 120-137).
Regarding claims 4-8, Johnson discloses the method of claim 1. Johnson further teaches using the MSBPs to deliver agents to a subject, tissue, or cell ([0006]).
Johnson differs from the instant claims in that Johnson does not specify that the cryo-TEM sample is flash-frozen in a cryogenic fluid prior to imaging and does not teach processing the image to generate a structural model, using single-particle cryo-electron microscopy, and or using cryo-electron tomography.
However, prior to the effective filing date, these methods were known as powerful ways to visualize samples essentially as they exist in solution (Stewart, Abstract and Kuntsche, Abstract). Stewart focuses on nanoparticles (Stewart, Abstract) and Kuntsche focuses on colloidal systems (Kuntsche, Abstract). Like Johnson, both Stewart and Kuntsche highlight systems for delivering agents (Johnson, [0356]; Stewart, pg. 3, col. 1, paragraph 2; Kuntsche, Abstract). Both Stewart and Kuntsche teach flash freezing aqueous samples in a cryogen to obtain a vitreous or amorphous state (Stewart, pg. 1, col. 2; Kuntsche, pg. 121, col. 1, paragraph 2) and show images produced by cryo-TEM. Stewart teaches that cryo-TEM can be used to visualize biological samples in near native state (Stewart, pg. 1, col. 1, paragraph 1). Stewart further teaches that single particle reconstruction can be used to determine the 3D structure of samples when the samples have homogeneous structures, whereas cryo-electron tomography (cryo-ET) can be used when samples have heterogenous structures (Stewart, Abstract). Stewart teaches that visualizing the 3D structure of samples is valuable for understanding how they interact with the human body in medical applications and with bulk materials in engineering applications (Stewart, pg. 3, col. 2, last paragraph). Likewise, Kuntsche teaches that the morphology of colloidal carriers in of utmost importance (Kuntsche, pg. 120, col. 1, paragraph 2) and that cryo-TEM is an indispensable tool for studying the size, shape, and internal structure of nanoparticular carrier systems and colloidal dispersions (Kuntsche, Abstract). Kuntsche also teaches obtaining 3D structural information with cryo-ET (Kuntsche, pg. 134, col. 1, last paragraph).
Given the disclosures of Stewart and Kuntsche, one of ordinary skill would have recognized that understanding the structure of materials for delivering agents is useful. One of ordinary skill would have also understood that cryo-TEM techniques such as single particle reconstruction and cryo-ET are useful for obtaining 3D structural information. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date to have characterized the MSBP of Johnson via the single particle reconstruction (claims 6-7) of Stewart and cryo-ET (claim 8) Stewart and Kuntsche in order to obtain 3D structural information. It would have further been obvious to prepare the sample by flash freezing a cryogenic fluid (claim 5) to obtain a sample comprising amorphous ice (claim 4) because Stewart and Kuntsche teach that this method is typical and provides structural insight of the material’s native state.
Regarding claims 9-10, Johnson discloses the method of claim 1.
Johnson differs from claims 9-10 in that the cryo-TEM image of Johnson is of the MSBP in water and does not contain the specific samples of claim 9 or claim 10.
However, Johnson teaches that the supramolecular complex may encapsulate an agent, such as a small molecule, a peptide, a protein, or a polynucleotide ([0199]). Therefore, it would have been obvious to one of ordinary skill to have prepared a MSBP composition comprising a peptide, a protein, or a polynucleotide because Johnson teaches it. Including a peptide, a protein, or a polynucleotide in the composition reads on wherein the sample comprises biomacromolecules (claim 9). A protein reads on wherein the sample comprises proteins (claims 10).
Furthermore, it would been obvious to image the composition comprising the MSBP and a peptide, a protein, or a polynucleotide using cryo-TEM given the teachings of Stewart and Kunctshe described above in the rejection of claims 5-8. Given the disclosures of Stewart and Kuntsche, one of ordinary skill would have recognized that understanding the structure of materials for delivering agents is useful. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date to have characterized the MSBP comprising a sample of Johnson via the cryo-TEM methods of Stewart and Kuntsche in order to study the size, shape, and internal structure of the materials.
Regarding claim 22, Johnson discloses the method of claim 1. Johnson further teaches using the MSBPs to deliver agents to a subject, tissue, or cell ([0006]).
Johnson differs from the instant claims in that the cryo-TEM image of Johnson is of a MSBP derived from a polymer without the portions indicated in rectangles below.
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However, Johnson teaches that the divalent linker (corresponding to the instant polymer) can comprise the segment shown below ([0271] and [0275]):
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Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date to have substituted the divalent linker used in “B-3” with
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because Johnson teaches this alternative. This substitution results in Lig-PEG-Lig’ with the structure of claim 22 where p and r are 2 and n is 30-60.
Furthermore, it would been obvious to image the composition comprising the modified MSBP using cryo-TEM given the teachings of Stewart and Kuntsche described above in the rejection of claims 5-8. Given the disclosures of Stewart and Kuntsche, one of ordinary skill would have recognized that understanding the structure of materials for delivering agents is useful. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date to have characterized any MSBP taught by Johnson via the cryo-TEM methods of Stewart and Kuntsche in order to study the size, shape, and internal structure of the materials.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AUDRA DESTEFANO whose telephone number is (703)756-1404. The examiner can normally be reached Monday-Friday 9-5.
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/AUDRA J DESTEFANO/Examiner, Art Unit 1766
/RANDY P GULAKOWSKI/Supervisory Patent Examiner, Art Unit 1766
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