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
Two information disclosure statement (IDS) submitted: one on 11/23/2022; and one on 12/12/2024. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
The listing of references in the specification (pages 26-29, 44-47, is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: “compound 6347615” and most other numerical identifiers of compounds in Figure 11 – which are claimed in claim 2 – are not mentioned anywhere else in the specification – see 112(b).
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-5 and 7-14), drawn to a flavanol, a linker coupled to the flavanol, and a carrier; in the reply filed on 12/19/2025, is acknowledged. The traversal is on the ground(s) that Groups I-III comprise the special technical feature and that Cano et al. fails to break unity by disclosing said technical feature. Applicant, however, does not specifically mention how the art of record fails to disclose the special technical feature uniting Groups I-III. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The requirement is still deemed proper and is therefore made FINAL.
Upon election of Group I, Applicant was further required to elect: (a) a single flavanol or flavanol analog; (b) a linker to be coupled with (a); and (c) a carrier to be couple with (b).
Applicant elected without traverse:
PNG
media_image1.png
331
452
media_image1.png
Greyscale
The elected linker was found to be free of the art in the context of linkage to a flavanol or flavanol analog (see claim interpretation below), therefore, the search was expanded to encompass any linker. For the purposes of applying art, the limitation of “a carrier” was also expanded to encompass any carrier.
Claims 16-19, 21, 23, and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/19/2025.
Status of the Claims
Claims 1-5, 7-14, 16-19, 21, 23 and 25 are pending in this application. Claims 6, 15, 20,
22, 24, and 26 have been cancelled by Applicant. Claims 16-19, 21, 23, and 25 are withdrawn from consideration. Claims 1-5 and 7-14 are under examination herein.
Examiner Notes
While claim 25 is not under examination herein, for the purposes of compact prosecution, Examiner would like to point out that the claim is currently presented as being dependent upon claim 24, which is a cancelled claim.
Claim Interpretation
Regarding claim 1, the specification does not specifically define the term “coupled” therefore, for the purposes of applying art, the term will be interpreted as encompassing covalent and non-covalent coupling. This interpretation is supported by the definition of “carriers” in the specification, which states: "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material (specifically mentioning polyols (PEG), and “non-toxic substances employed in pharmaceutical formulations” (which encompasses ascorbic acid) (see page 11 of the spec.).
The instant specification provides no definition for the term “flavanol analog”. For the purposes of applying art, a “flavanol analog” will be understood as any compound having the following general cores (or similar chroman core structures), as disclosed in the art by Luo et al. (Molecules, 2022, 27, 719).
PNG
media_image2.png
205
1088
media_image2.png
Greyscale
Chroman core:
PNG
media_image3.png
107
157
media_image3.png
Greyscale
Claim Objections
Claim 11 is objected to because of the following informalities: The comma after “protein of interest” should be removed.
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.
Claims 2-3 and 11 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.
Claims 2-3 are rejected for citing elements from tables J and L, respectively, which reference other parts of the specification, such as other tables and figures. Applicant is advised that, as stated in MPEP 2173.05(s), claims should be complete to themselves and the reference to tables renders the claims incomplete. Claims which recite figures or tables are only permitted in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into a claim.
Claim 2 is also rejected as indefinite because, Table J refers to “compounds on the x-axis of Figure 11”, some of which are referred to with numerical identifiers (IDs), such as “6347615”, for example. These number IDs do not give an obvious result after a google search; they do not seem to be known in the art; and are not clearly disclosed in the spec. Therefore, the metes and bounds of the claim are unclear.
Further regarding claim 2, the phrase “Examples of flavanols or flavanol analogs” (table heading – see below) renders the claim indefinite because it is unclear whether the limitation(s) following the phrases are part of the claimed invention or mere exemplary elements. See MPEP § 2173.05(d).
PNG
media_image4.png
292
570
media_image4.png
Greyscale
Further regarding claim 3, the phrase “Examples of linkers” (table heading – see below) renders the claim indefinite because it is unclear whether the limitation(s) following the phrases are part of the claimed invention or mere exemplary elements. See MPEP § 2173.05(d). For the purposes of applying art, the claim will be given the broadest reasonable interpretation, as encompassing any linker, whether exemplified in the table or not.
PNG
media_image5.png
107
571
media_image5.png
Greyscale
Regarding clam 11: (i) the limitation "the said amyloid" in line 4 lacks antecedent basis. Is applicant referring to “the amyloid protein of interest” from line 3?; (ii) the term “the target fibril” lacks antecedent basis; (iii) the limitation “additional mode of amyloid inhibition” lacks antecedent basis – no other “modes of inhibition” are specifically mentioned in the claims; and (iv) the term “potentially” renders the claim indefinite, because there is a question as to whether the limitations following the term are required or not.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2-3 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 is rejected for failing to further limit claim 1, from which it depends. Claim 1, speaks to an agent comprising a flavanol or flavanol analog. Claim 2, refers to the agent wherein the flavanol or flavanol analog is a compound selected from Table J; Table J includes the compounds of Table A, which include, for example, BMS-201038, docarpamine, etc. (structures shown below for convenience). These compounds, as understood in the art, are neither flavanols, nor flavanol analogs – see claim interpretation.
PNG
media_image6.png
153
182
media_image6.png
Greyscale
(BMS-201038)
PNG
media_image7.png
78
183
media_image7.png
Greyscale
(docarpamine)
Table J also cites Table B, which contains compounds that are neither flavanols, nor flavanol analogs as understood in the art – see claim interpretation. For example, 2-(7-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-1H-isoindole-1,3(2H)-dione and N-(tert-butyl)-N-(difluoromethyl)-4-methylbenzenesulfonamide, etc.
Table J also cites “compounds on the x-axis of Figure 11”. The x-axis of Figure 11 contains DMSO and CNS-set 7220009 (structure shown in top left of graph in Fig. 11), neither of which is a flavanol or flavanol analog – see claim interpretation.
Claim 3 is rejected for depending upon the limitations of claim 2.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 7, 9-10, and 12-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cano et al. (Journal of Controlled Release, 301, 2019, 62–75 – previously cited) (“Cano”).
Regarding claim 1-4, Cano discloses epigallocatechin-3-gallate (EGCG) (elected flavanol species) as a candidate for the treatment of Alzheimer’s disease (AD), and as having limited bioavailability and effectiveness due to its instability (abstract). Cano discloses EGCG displayed increased stability when formulated as dual drug loaded PEGylated poly-(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) (reading on claim 4; and on a carrier “coupled” to a linker “coupled” to a flavanol – see claim interpretation, and 112(b) for claim 3); with the NP formulation also comprising ascorbic acid (AA) (which can also act as a carrier – see claim interpretation). Cano refers to their formulation as EGCG/AA NPs, for short (page 63, col. 2, para. 1-2).
Regarding claims 7 and 9, Cano discloses a PEGylated nanoparticle carrier.
Regarding claim 10, Cano discloses a monodisperse population a hydrodynamic particle size (Zav) of 124.8 ± 5.2 nm (page 66, col. 1, section 3.1), which is encompassed by the instantly claimed range of 4-150 nm, and therefore anticipates the claim.
Regarding claim 12, Cano discloses administration of EGCG/AA NPs resulted in a marked increase in synapses, as judged by synaptophysin (SYP) expression, and reduction of neuroinflammation as well as Aβ plaque burden and cortical levels of soluble and insoluble Aβ (1-42) peptide. Cano discloses that EGCG inhibits TAU aggregation and Aβ accumulation.
Regarding claim 13, Cano discloses that both empty NPs and EGCG/AA NPs all induced tight junction disruption and opened the blood brain barrier (BBB) in vitro and ex vivo (abstract).
Regarding claim 14, Cano discloses oral administration of their EGCG/AA NP formulation in mice, specifically in the context of treating AD – thus anticipating the instant composition comprising the agent of claim 1 (abstract).
Further regarding claims 12-14, Applicant is advised that A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. In the present case, claims 12-14 are directed to the agent of claim 1, and thus the limitations outlined after “wherein” in each of these claims are not further limiting. If the prior art structure is capable of performing the intended use, then it meets the claim. Note: MPEP 2111.02. Applicant is further advised that products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
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 1-5 and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Cano et al. (Journal of Controlled Release, 301, 2019, 62–75 – previously cited) (“Cano”); as applied to claims 1-2, 4, 7, 9-10, and 12-14; in view of Tomitaka et al. (Drug Discovery Today, 24, 2019, 873-882) (“Tomitaka”).
The teachings of Cano are disclosed in the 102-section above and incorporated herein.
While Cano doesn’t specifically teach: (i) iron oxide nanoparticle (IONP) carriers, such as the elected ferumoxytol (claim 5); or (ii) dextran or carboxy-dextran as the coating for the carrier (claims 7-8); the teachings of Tomitaka are relied upon for these disclosures.
Tomitaka teaches that multifunctional magnetic nanoparticles are investigated not only for site-specific drug delivery but also for theragnostic applications aiming for an effective CNS therapy (abstract). Tomitaka specifically discloses enhanced blood brain barrier (BBB) transmigration of various magnetic nanoparticles using the magnetic targeting approach and that in vitro and in vivo toxicity studies of these nanoparticles showed minimum toxicity in CNS cells and small animals. “In addition to the brain delivery across the BBB, targeting specificity in CNS diseases can be introduced by functionalizing IONPs with the ligands specific to the surface receptors of the diseases. For the detection and treatment of AD, some molecules that specifically bind to amyloid plaques have been used as targeting ligands” (page 874, col. 2, para. 2) (reading on claim 11). Tomitaka teaches ferumoxytol as one of the few IONPs that have been clinically approved as MRI contrast agents and whose use has not been discontinued (para. bridging pages 879-880).
Therefore, regarding claims 1-5, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to modify Cano’s AD treatment agent comprising EGCG/ AA NP (flavanol coupled to a linker coupled to a carrier) by incorporating an IONP carrier, such as ferumoxytol, in view of Tomitaka. One of ordinary skill would have been motivated to do so because Cano discloses that EGCG is a candidate for the treatment of Alzheimer’s disease (AD), which has limited bioavailability and effectiveness due to its instability (abstract); further because Cano discloses one way to remedy this stability issue is to formulate EGCG as a drug loaded PEGylated poly-(lactic-co-glycolic acid) (PLGA) nanoparticle (NP), which showed improved delivery across the BBB. One would have been further motivated because Tomitaka discloses the benefits of surface-engineered IONPs for theranostic applications aiming for effective CNS therapies while allowing for targeted drug delivery and for imaging of the brain (abstract) – Tomitaka specifically mentions AD as one of these CNS diseases (page 873, col. 1). One of ordinary skill would have had a reasonable expectation of success because Cano discloses that their NP formulation improved bioavailability; and because Tomitaka discloses ferumoxytol as one of the few IONPs that have been clinically approved and been successfully used for the treatment and imaging of a number of CNS diseases (table 1, page 879). Therefore, one of ordinary skill would have been motivated to prepare an EGCG-IONP formulation with ferumoxytol as a carrier to transport the flavanol AD therapeutic across the BBB and deliver it in the afflicted subject’s brain. A person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2143(E) KSR, 550 U.S. at 421, 82 USPQ2d at 1397.
Applicant is advised that the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art (In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).” See MPEP2144.06. It is therefore obvious to provide a mixture of the two agents.
Regarding claims 7-8, Tomitaka discloses that IONP carriers may be coated with dextran or carboxy-dextran (page 874, col. 1, lines 20-22).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Cano et al. (Journal of Controlled Release, 301, 2019, 62–75 – previously cited) (“Cano”); in view of Tomitaka et al. (Drug Discovery Today, 24, 2019, 873-882) (“Tomitaka”); as applied to claims 1-5 and 7-8; further in view of Luo et al. (Front. Cell. Neurosci., 2020, 14:21, 11 pages – Pub Date: Feb. 28th, 2020) (“Luo”).
The teachings of Cano and Tomitaka are disclosed above and incorporated herein.
While Cano in view of Tomitaka does not teach their agent further comprising an anti-amyloid antibody coupled to the carrier (claim 11); the teachings of Luo are relied upon for these disclosures.
Luo teaches their USPIO-PHO (iron nanoparticles (USPIO) coupled to a peptide C-IPLPFYN-C (PHO)), could cross the BBB of mice and accumulate in the brain with high affinity and low toxicity. Luo teaches that their NPs had the potential to label amyloid plaques in the brain (page 6, col. 1-2, IONP in the diagnosis of AD in vivo – section). Luo discloses anti-Aβ PP antibody-conjugated SPION have been synthesized and are known in the art, specifically disclosing DDNP-SPIONs; curcumin conjugated SPIOs; as well as their USPIO-PHO, which showed good correlation with anti-amyloid β antibody and Perls’-DAB staining.
Therefore, regarding claim 11, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to prepare an agent comprising Cano’s EGCG AD treatment in Tomitaka’s IONP carrier formulation (ferumoxytol), further comprising an anti-amyloid antibody coupled to the IONP carrier, in view of Luo. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because of Cano’s and Tomitaka’s disclosure of an IONP-EGCG formulation for the treatment, diagnosis, and monitoring of AD disease with MRI techniques; because of Tomitaka’s teaching that targeting specificity in CNS diseases can be introduced by functionalizing IONPs with the ligands specific to the surface receptors of the diseases; and further because Luo discloses their IONP nanoparticle comprising a peptide (PHO) which acts as an anti-amyloid antibody, allowing for the detection of amyloid plaques in the brain.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5.
Examiner interviews are available via telephone and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L. Klinkel can be reached at (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627