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 .
DETAILED ACTION
Claims 1-21 are pending in the Claim Set filed 10-30-2025.
Claims 8-14 and 18-21 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention.
Herein, claims 1-7 and 15-17 are for examination.
Withdrawn Rejections
The rejection of claims 1-2, 4-7 and 15-17 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the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention is withdrawn in view of the claim amendments.
Claim Rejections - 35 USC § 112-Scope of Enablement
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 rejection of claims 1-7 and 15-17 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an L-amino acid molecules are selected from the group consisting of L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, and L-valine, the claimed invention does not reasonably provide enablement for amino acid-functionalized nanoparticle, comprising amino acid molecules selected from the group consisting of D-amino acids: D-histidine, D-isoleucine, D-leucine, D-lysine, D-methionine, D-phenylalanine, D-threonine, D-tryptophan, and D-valine. is maintained and made again. The rejection has been reformulated in view of the claim amendments.
Instant Claim 1 in the Claim Set filed 10-30-2025 recites:
An amino acid-functionalized nanoparticle, comprising:
i) a nanoparticle having a dimension in the range of units of 10 nanometers to150 nanometers, and having an external surface; and
ii) a plurality of amino acid molecules conjugated to the external surface of the nanoparticle, the amino acid molecules having a chemical property that can induce a cancer cell to ingest the functionalized nanoparticle;
wherein said nanoparticle is a mesoporous silica nanoparticle and/or other ROS generating nanoparticle; and
wherein said amino acid molecules are selected from the group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine; and wherein said amino acid-functionalized nanoparticle is drug-free and has anti-cancer activity by inducing oxidative stress.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims without undue experimentation. MPEP 2164.01(a), citing In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), sets out the factors to consider whether experimentation is undue, which include:
The nature of the invention. The claims are drawn to an amino acid-functionalized nanoparticle.
The breadth of the claims. Giving the claims their broadest reasonable interpretation: Claim 1 would encompass amino acid molecules selected from the group consisting of DL- histidine, DL- isoleucine, DL- leucine, DL-lysine, DL- methionine, DL-phenylalanine, DL- threonine, DL- tryptophan, and DL-valine. Therefore, the stereoisomers DL-amino acid (s) renders the scope of the claims unreasonably broad.
The level of one of ordinary skill in the mesoporous silica nanoparticle having a chemical property that can induce a cancer cell to ingest the functionalized nanoparticle arts is relatively high. It is the Examiner's position that a significant portion of that skill can arise from advanced degrees, such that the level of ordinary skill would contemplate at least a master's degree in an appropriate discipline and/or a medical degree along with three or more years of clinical experience.
The level of predictability in the art. The amino acid molecules selected from the group consisting of consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine encompass both stereoisomers of DL- histidine, DL- isoleucine, DL- leucine, DL-lysine, DL- methionine, DL-phenylalanine, DL- threonine, DL- tryptophan, and DL-valine. However, Wu et al. (Potent-By Design: Amino Acids Mimicking Porous Nanotherapeutics with Intrinsic Anticancer Targeting Properties, published 7/2020, of record) teaches mesoporous silica nanoparticles having a plurality of amino acids conjugated to the surface, where the amino acids are all L-stereoisomers (Abstract; Figure 2, page 3; 4. Experimental Section, p/8). Wu teaches nano porous amino acid mimics (Nano-pPAAM) could selectively kill cancer cells by targeting the L-type amino acid transporter (LAT-1) that is overexpressed in cancer cells (p.2; left col., bottom of page; p.5, left col. bottom of page). Also, Chien et al (Reevaluating the Substrate Specificity of the L‑Type Amino Acid Transporter (LAT1). J. Med. Chem. p/7358, 2018) teaches amino acid enantiomers (D vs L) have different structure activity relationships (SAR) although the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes (Abstract, p.7366; See Tables 1-3). Accordingly, a person of skill in the art would have to conduct undue experimentation to determine whether a nanoparticle having a plurality of D- amino acids and is drug-free, would bind to cancer cells and show antitumor activity for a specific cancer.
The amount of direction provided by the inventor. While the specification provides guidance and examples of the syntheses of Nano-PAAMs for each amino acid selected from: L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, and L-valine, (p.11, lines 11-20; Figure 2A) and their distinct anticancer activity (cell viability: figure 2d); A small library consisting of dimensions of 9 essential amino-acid (EAA) based Nano-PAAM (30 nm) were synthesized to examine its anticancer effects (Specification at pages 2: summary of Invention through page 3, lines 1-2); In some embodiments, the nanoparticle has a dimension in the range of 10-150 nm, preferably about 30 nm (Specification page 4, lines 6-7); In some embodiments of the method of production, the nanoparticle has a dimension in the range of 10-80 nm, preferably about 30 nm (Specification page 4, lines 25-26); Drawings filed 11/24/2021: See Figure 2A: shows nine essential amino acids (EAAs), all have L-configuration. However, there is no guidance or examples in the specification/disclosure of the synthesis and/or anti-cancer activity for the D- stereoisomer of the amino acids: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Therefore, the limitation: wherein said amino acid molecules are selected from the group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine, that is recited in claim 1 in in the Claim Set filed 1/06/2025 renders the scope of instant claims unreasonably broad.
The quantity of experimentation needed to make or use the invention. Because amino acid molecules are selected from the group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine, are broadly claimed, coupled with a lack of guidance and direction provided by the instant disclosure, a skilled artisan could not practice the invention commensurate with the full scope of the claims without undue experimentation.
Response to Arguments
Applicants state that according to the Office Action, there is no guidance or examples in the specification of the synthesis and/or anti-cancer activity for the D-stereoisomer of the amino acids, thus a person skilled in the art wound not practice the invention within the full scope of the claims without undue experimentation.
Applicants argue that Chien et al. discloses the substrate specificity of LAT1, and indicates "the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes." (see page 2, lines 7-8). Specifically, Chien et al. discusses LAT1 activity on D vs L amino acid substrates (see page 9), and discloses that "we conclude from our assays that LAT1 is not stereoselective with regards to the rate of transporting amino acids, although the manner in which the D and L isomers bind to LAT1 appears to be quite different given their relative IC5os." (see page 10, first sentence of the second paragraph). In the Conclusion section, Chien et al. states "the transporter is capable of transporting both L and D enantiomers, albeit with varying IC5os depending on the amino acid. These" (see page 13). Thus, in view of Chien et al. as a whole, one skilled in the art would understand that although different enantiomers (D vs L) may result in different binding activities of the amino acids toward LAT1, LAT1 is still able to transport both enantiomers and thus is not stereoselective. Indeed, the disclosure of Chien et al. is opposite to the allegation of the Office Action, and supports that based on the effects of tested L-amino acids and common general knowledge, one skilled in the art can expect the D-amino acids to achieve similar effects as the tested L-amino acids-that both isomers are capable of inducing oxidative stress in regards to
Applicant’s arguments have been fully considered but they are not persuasive, because the teachings of Chien support the fact that undue experimentation would be required to evaluate and separately determine the activities for both D- and L- essential amino acids (EAAs: (histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine (Specification at page 4) in regards to said nanoparticle is a mesoporous silica nanoparticle and/or other ROS generating nanoparticle; and wherein said amino acid molecules are selected from the group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine; and wherein said amino acid-functionalized nanoparticle is drug-free and has anti-cancer activity by inducing oxidative stress in any and all cancers as broadly as claimed. Moreover, Chien’s conclusion of no stereoselectivity is fully supported by experimental evidence for D, L- enantiomers. Whereas, Specification is lacking a single example where a D-essential amino acid demonstrates biological effect for inducing oxidative stress and having anti-cancer activity in all cancers would necessarily warrant undue experimentation, since the specification only provides guidance and examples of the syntheses of Nano-PAAMs for each amino acid selected from: L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, and L-valine, (p.11, lines 11-20; Figure 2A ) that bind LAT-1 overexpressed on cancer cells and have distinct anticancer activity (cell viability: figure 2d). Accordingly, there is no guidance or direction, or working examples in the specification/disclosure directed to the D- essential amino acids of that include: D-histidine, D-isoleucine, D-leucine, D-lysine, D-methionine, D-phenylalanine, D-threonine, D-tryptophan, and D-valine. Specification at page 3 states: The working principle of the said invention is premised on (i) the intrinsically high demand of cancer cells for amino acids (AAs) to fuel their metabolism and (ii) their susceptibility to oxidative stress-induced cell death. Further, Specification states a small library consisting of dimensions of 9 essential amino-acid (EAAs) based Nano-PAAM (30 nm) were synthesized to examine its anticancer effects (Specification at pages 2: summary of Invention through page 3, lines 1-2). Moreover, it is known in the art of Chien et al (Reevaluating the Substrate Specificity of the L‑Type Amino Acid Transporter (LAT1). J. Med. Chem. p/7358, 2018) that amino acid enantiomers (D vs L) have different structure activity relationships (SAR) that exhibit different binding modest toward LAT1 transporter. Thus, a person of skill in the art would have to determine whether each D- and/or L- stereoisomer for all amino acids as instantly claimed shows and/or substantially suggests anti-cancer activity in all cancers by inducing oxidative stress. Because amino acid molecules are selected from the group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine, are broadly claimed, coupled with a lack of guidance and direction provided by the instant disclosure, a skilled artisan could not predictably practice the invention commensurate with the full scope of the claims without undue experimentation.
Conclusions
No claim is allowed.
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.
Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Thurman Wheeler whose telephone number is (571)-270-1307. The examiner can normally be reached Monday-Friday 10:00am-6:00pm EST.
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/T.W./ Examiner, Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619