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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Nucleotide and/or Amino Acid Sequence Disclosures
The sequence listings in this application have been entered.
Claim Objections – Claim Numbering
The numbering of claims is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not).
In this case, the numbering of the claims skips from claim 110 to claim 112, with claim 111 being skipped.
For the purposes of examination under prior art, the examiner will proceed with examination using the claim numbers provided, and will proceed as if claim 111 has been cancelled rather than skipped.
Claim Interpretation
Instant claim 95 recites a gamma polyglutamated raltitrexed. This claim requirement does not exclude a polyglutamated raltitrexed that is both alpha polyglutamated and gamma polyglutamated.
Note Regarding Multiple Numerical Ranges in Claims
Various claims recite multiple numerical ranges in the same claim. One example of this is claim 101, which recites a broad size range of 20 nm to 500 nm, a narrower size range of 20 nm to 200 nm, and a narrow size range of 80 nm to 120 nm. The examiner notes that the presence of multiple numerical limitations in the alternative do not render the claim indefinite. The mere fact that a compound may be embraced by more than one member of a Markush group recited in the claim does not necessarily render the scope of the claim unclear. For example, the Markush group, "selected from the group consisting of amino, halogen, nitro, chloro and alkyl" should be acceptable even though "halogen" is generic to "chloro." See MPEP 2173.05(h)(I), last paragraph in section. In this case, for similar reasons, a Markush group comprising both a broad size range of 20 nm to 500 nm and a narrower size range of 20 nm to 200 nm recited as alternatives is definite even though 20 nm to 500 nm is generic to narrower limitations such as 20 nm to 200 nm. In a similar vein, the multiple ranges of number of glutamyl groups in the “D” stereochemistry in claim 100, or multiple ranges of pH in claim 105, or multiple ranges of number of molecules in claim 106 is understood by the examiner to be definite.
Claim Rejections - 35 USC § 112(a) – 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 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.
Claim 112 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for administering the recited liposome, does not reasonably provide enablement for treating an infectious disease with gamma polyglutamated raltitrexed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. See MPEP 2164.01(a). The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by MPEP 2164.01(a) and are set forth below.
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved; see MPEP 2164.03. Keeping that in mind, the factors set forth in MPEP 2164.01 are relevant to the instant fact situation for the following reasons:
1. The nature of the invention, state and predictability of the art, and relative skill level (B)-(E)
The invention relates to a method for treating an infectious disease by administering gamma polyglutamated raltitrexed in a liposome delivery vehicle. The relative skill of those in the art is high, that of an MD or PhD. That factor is outweighed, however, by the unpredictable nature of the art. As illustrative of the state of the art, the examiner cites Product Monograph (Obtained from https://pdf.hres.ca/dpd_pm/00040629.PDF on 26 August 2026, originally published 8 August 2017, 23 printed pages). Product Monograph is a summary of well-known information regarding raltitrexed, which is also known as Tomudex. As an initial matter, Product Monograph teaches that raltitrexed is a cancer chemotherapy agent, as of page 2 of Product Monograph, and does not teach the use of raltitrexed for treating infectious diseases. Product monograph also teaches that raltitrexed results in leucopenia in a significant fraction of patients (i.e. the term “leucopenia”, which is also spelled “leukopenia”, refers to low concentrations of leucocytes in blood, wherein leucocytes are white blood cells), as of Product monograph, page 8, relevant text reproduced below.
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Product Monograph teaches that neutropenia is associated with raltitrexed administration, as of Product Monograph, page 5, second to last paragraph, relevant text reproduced below.
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Neutropenia, which is a lack of neutrophils, results in increased risk of infection, as taught by Ing (Canadian Family Physician, Vol. 30, September 1984, pages 1835-1839), as of the abstract.
As such, the prior art indicates that administration of raltitrexed would have resulted in an increased risk of infection in a significant number of patients due to leucopenia and/or neutropenia and would not have resulted in treating an infectious disease. As such, in view of these teachings, there would have been no reasonable expectation that raltitrexed could have predictably treated an infectious disease in the absence of undue experimentation.
The breadth of the claims (A)
Claim 112 is especially broad because it is drawn to the full scope of infectious diseases and the full scope of dose ranges.
3. The amount of direction or guidance provided and the presence or absence of working examples (F)-(G)
The instant specification includes various examples; however, these examples appear to be drawn to using liposome-encapsulated gamma polyglutamated raltitrexed to treat cancer. See e.g. page 191, paragraph 00411, in which the recited liposome-encapsulated gamma polyglutamted raltitrexed is used to kill cancer cells in vitro. There are no working examples drawn to liposome-encapsulated gamma polyglutamted raltitrexed for treating infectious disease.
As such, the specification provides no direction or guidance for practicing the claimed invention in its “full scope”. No reasonably specific guidance is provided concerning useful therapeutic protocols for treating an infectious disease with liposome-encapsulated gamma polyglutamted raltitrexed, and no example of in vitro testing drawn to this matter has been disclosed.
4. The quantity of experimentation necessary (H)
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed liposome-encapsulated gamma polyglutamted raltitrexed could be predictably used to treat infectious disease, as inferred by the claim and contemplated by the specification, in the absence of undue experimentation. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the claimed invention in its “full scope” a person of ordinary skill in the art would have to engage in undue experimentation, with no reasonable expectation of success.
Non-Statutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 95-110 and 113 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12,239,734. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
The instant claims are drawn to a liposome composition comprising gamma polyglutamated raltitrexed encapsulated by a liposome. This liposome is pegylated but lacks a targeting moiety having affinity for a surface antigen, lacks a cell penetrating peptide, and lacks a mitochondria penetrating peptide. The liposome has a zeta potential that is zero or negative and is capable of delivery the gamma polyglutamated raltitrexed directly into a cell. The gamma polyglutamated raltitrexed has 3-12 glutamyl groups.
The conflicting claims are drawn to a liposome composition comprising gamma polyglutamated raltitrexed encapsulated by a liposome. This liposome is pegylated but lacks a targeting moiety having an affinity for a surface antigen, lacks a cell penetrating peptide, and lacks a mitochondria penetrating peptide. The liposome has a zeta potential that is zero or negative and is capable of delivery the gamma polyglutamated raltitrexed directly into a cell. The gamma polyglutamated raltitrexed has 2-10 glutamyl groups.
The instant and conflicting claims differ because the instant claims recite 3-12 glutamyl groups, whereas the conflicting claims recite 2-10 glutamyl groups. While the prior art does not disclose the exact claimed values but does overlap: in such instances even a slight overlap in range establishes a prima facie case of obviousness. See MPEP 2144.05(I). This is sufficient to establish a prima facie case of obviousness-type non-statutory double patenting.
The instant and conflicting claims also differ because various instant claims recite the stereochemistry of the glutamyl groups, such as instant claims 99-100, and this feature is not recited by the conflicting claims. Nevertheless, individual stereoisomers are prima facie obvious over each other or a mixture of stereoisomers. See MPEP 2144.09(II), first paragraph in section as well as MPEP 2143(I)(B), Example 8.
Claims 95-110 and 113 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 12,246,015. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
The instant claims are drawn to a liposome composition comprising gamma polyglutamated raltitrexed encapsulated by a liposome. This liposome is pegylated but lacks a targeting moiety having affinity for a surface antigen, lacks a cell penetrating peptide, and lacks a mitochondria penetrating peptide. The liposome has a zeta potential that is zero or negative and is capable of delivery the gamma polyglutamated raltitrexed directly into a cell. The gamma polyglutamated raltitrexed has 3-12 glutamyl groups.
The conflicting claims are drawn to a liposome comprising alpha polyglutamated raltitrexed having 2-10 glutamyl groups. This liposome is not pegylated, as of conflicting claim 11, and has a zero or negative zeta potential, as of conflicting claim 17. The liposome of the conflicting claims appears to lack a targeting moiety having a specific affinity for a surface antigen on a target cell, as of conflicting claim 1.
The instant and conflicting claims differ because instant claim 1 is drawn gamma polyglutamated raltitrexed whereas conflicting claim 1 is drawn to alpha polyglutamated raltitrexed. Nevertheless, conflicting claim 4, part (e) recites the following, which is reproduced below.
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As such, the conflicting claims appear to recite a polyglutamated raltitrexed which is both gamma polyglutamated and alpha polyglutamated; this appears to be within the claim scope.
The instant and conflicting claims also differ because the instant claims recite that the liposome is capable of delivering the payload directly into a cell. This is not specifically recited by the conflicting claims. Nevertheless, the subject matter of the conflicting claims is drawn to the same liposome with a polyglutamated antifolate. As such, the skilled artisan would have expected that the liposome of the conflicting claims would have been capable of delivering the payload directly into a cell even if that feature was not specifically recited by the conflicting claims.
The instant and conflicting claims also differ because various instant claims recite the stereochemistry of the glutamyl groups, such as instant claims 99-100, and this feature is not recited by the conflicting claims with respect to the gamma polyglutamated raltitrexed. (The examiner notes that this feature is recited in conflicting claim 5, but it appears to apply to the alpha polyglutamated raltitrexed rather than the gamma polyglutamated raltitrexed). Nevertheless, individual stereoisomers are prima facie obvious over each other or a mixture of stereoisomers. See MPEP 2144.09(II), first paragraph in section as well as MPEP 2143(I)(B), Example 8.
Claims 95-110 and 113 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, and 95-114 of copending Application No. 19/024,252 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
The instant claims are drawn to a liposome composition comprising gamma polyglutamated raltitrexed encapsulated by a liposome. This liposome is pegylated but lacks a targeting moiety having affinity for a surface antigen, lacks a cell penetrating peptide, and lacks a mitochondria penetrating peptide. The liposome has a zeta potential that is zero or negative, and is capable of delivery the gamma polyglutamated raltitrexed directly into a cell. The gamma polyglutamated raltitrexed has 3-12 glutamyl groups.
The copending claims are drawn to a liposome composition comprising polyglutamated raltitrexed which is pegylated and does not contain a targeting moiety. The liposome also further encapsulates one or more nonpolyglutamated antifolate. Copending claim 102 recites a zero or negative zeta potential.
The instant and copending claims differ because the copending claims recite a nonpolyglutamated antifolate encapsulated in the liposome in addition to the gamma polyglutamated raltitrexed. However, this difference is not sufficient to overcome the applied double patenting rejection. This is because the “comprising” language of the instant claims does not exclude additional unrecited elements such as the nonpolyglutamated antifolate. The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See MPEP 2111.03(I).
The instant and copending claims also differ because the instant claims recite that the liposome is capable of delivering the payload directly into a cell. This is not specifically recited by the copending claims. Nevertheless, the subject matter of the copending claims is drawn to the same liposome with a polyglutamated antifolate. As such, the skilled artisan would have expected that the liposome of the copending claims would have been capable of delivering the payload directly into a cell even if that feature was not specifically recited by the copending claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 95-110 and 113 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, and 95-120 of copending Application No. 18/947,593 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
The instant claims are drawn to a liposome composition comprising gamma polyglutamated raltitrexed encapsulated by a liposome. This liposome is pegylated but lacks a targeting moiety having affinity for a surface antigen, lacks a cell penetrating peptide, and lacks a mitochondria penetrating peptide. The liposome has a zeta potential that is zero or negative, and is capable of delivery the gamma polyglutamated raltitrexed directly into a cell. The gamma polyglutamated raltitrexed has 3-12 glutamyl groups.
Copending claims 1 and 3 recite a pegylated liposome encapsulating a gamma polyglutamated antifolate containing 3-12 glutamate groups, wherein said antifolate may be raltitrexed. The liposome may have a zeta potential of zero or a zeta potential that is negative, as of copending claim 101. While the copending claims do not appear to exclude a targeting ligand, cell penetrating peptide, or mitochondria penetrating peptide, no such features are positively recited by the copending claims and as such would not appear to be present.
The instant and copending claims also differ because the instant claims recite that the liposome is capable of delivering the payload directly into a cell. This is not specifically recited by the copending claims. Nevertheless, the subject matter of the copending claims is drawn to the same liposome with a polyglutamated antifolate. As such, the skilled artisan would have expected that the liposome of the copending claims would have been capable of delivering the payload directly into a cell even if that feature was not specifically recited by the copending claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
No Prior Art Rejection
The instant claims are not subject to a prior art rejection. The examiner presents the following rationale for not rejecting the instant claims over prior art. This rationale is similar to that presented in the reasons for allowance in the notice of allowance mailed on 7 October 2024 in parent application 16/967,293.
Barenholz Reference – Overview: As relevant prior art, the examiner cites Barenholz (Journal of Controlled Release 160 (2012), pages 117–134). Barenholz is drawn to a liposome known by the trade name of “Doxil®”, as of Barenholz, page 117, title and abstract. This liposome is actually a PEGylated liposome encapsulating doxorubicin, as of Barenholz, page 117, abstract and page 118, right column, bottom paragraph and page 119, left column, second paragraph. The liposome of Barenholz is made from phospholipids, cholesterol, and PEG-DSPE, which is a PEGylated lipid, as of Barenholz, page 120, left column, Table 1. The phospholipids of Barenholz appear to be phosphatidylcholine, as of the abstract of Barenholz. The liposome of Barenholz appears to have a negative zeta potential, as of Barenholz, page 128, right column, relevant paragraph reproduced below with highlighting of a term by the examiner.
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The liposome of Barenholz also does not contain a targeting moiety having specific affinity for a surface antigen on a target cell, does not contain a cell-penetrating peptide, and does not contain a mitochondria-penetrating peptide.
Barenholz differs from the claimed invention for the following two reasons.
First, the anti-cancer agent of Barenholz differs from the claimed anti-cancer agent. Barenholz teaches doxorubicin as the anti-cancer agent, whereas the instant claims require gamma polyglutamated raltitrexed as the anti-cancer agent.
Secondly, Barenholz does not teach that the liposome is capable of active agent directly into a cell.
Barenholz Does Not Teach Delivering Active Agent Directly into a Cell: Barenholz teaches the following on page 126, left column, second paragraph, relevant text reproduced below.
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The examiner understands the above-reproduced text to indicate that the product known as Doxil operates by releasing active agent (doxorubicin) into the tumor interstitial fluid, wherein the doxorubicin is subsequently uptaken by cancer cells. This would appear to indicate that in the case of the liposome of Barenholz, the liposome is not capable of delivering the active agent directly into a cell. This is because, as Barenholz teaches that the doxorubicin is first released to the tumor interstitial fluid, its uptake by a cell is not direct.
In view of this teaching, the examiner takes the position that even if, purely en arguendo, the skilled artisan was motivated to have substituted gamma polyglutamated raltitrexed in place of the doxorubicin of Barenholz to be used in the liposome of Barenholz, there would have been no reasonable expectation that the resultant liposome would have been capable of inherently delivering the gamma polyglutamated raltitrexed directly into a cell. The examiner must provide rationale or evidence to show inherency (e.g. of the capability of direct delivery of active agent into a cell); however, in this case, the evidence would appear to go against inherency. See MPEP 2112(IV). Reasons going against inherency are that it is generally cationic liposomes that deliver active agent directly to a cell; however, the claimed invention is a neutral or anionic liposome given the claim limitation drawn to zeta potential. This is explained in greater detail below.
Barenholz Appears to Teach Away: Additionally, Barenholz may actually teach away from formulating the claimed invention. Barenholz indicates that cancer drugs which are not capable of being uptaken by cells would not appear to show a benefit of being delivered by liposomes. See the text reproduced above from Barenholz, page 126, left column, wherein Barenholz points out cisplatin as an example of a drug that is not capable of being uptaken by cells when presented in the interstitial fluid near where the cells are located. Barenholz points out that the art indicates no benefit of the use of liposomes to deliver cisplatin.
The instant specification would appear to indicate that polyglutamated raltitrexed in the absence of the liposome or other cell penetrating agents would not have been able to have crossed the cell membrane; see the instant specification on pages 1-2, paragraph 0005. As such, the examiner takes the following position: Barenholz teaches a benefit for administering drugs via liposome that can cross the cell membrane such as doxorubicin; however specifically points out the lack of a benefit for drugs that cannot cross the cell membrane such as cisplatin. As such, the skilled artisan would have therefore expected that gamma polyglutamated raltitrexed would have behaved more similarly to cisplatin as compared with doxorubicin. Therefore, the skilled artisan would not have expected a benefit for administering gamma polyglutamated raltitrexed via liposome for the same reason that no benefit was obtained for administering cisplatin in the form of a liposome. As such, the art would have taught away from administering gamma polyglutamated raltitrexed via a liposome that is not targeted and does not comprise an element for intracellular delivery such as a cationic lipid, cell penetrating peptide, or mitochondria penetrating peptide.
Therefore, proceeding contrary to the accepted wisdom is evidence of non-obviousness. See MPEP 2145(X)(D)(3). In this case, the accepted wisdom would have been that there would have been no benefit to administering gamma polyglutamated raltitrexed via a liposome with the recited lipid composition and liposomal structure. However, applicant appears to have administered gamma polyglutamated raltitrexed via the recited liposome and to have achieved the benefit of the capability of direct delivery into cells such as cancer cells. This would appear to support a conclusion of non-obviousness based upon the rationale set forth in MPEP 2145(X)(D)(3).
Niyikiza Reference: As an additional relevant reference, the examiner cites Niyikiza et al. (WO 2016/025882 A2). Niyikiza et al. (hereafter referred to as Niyikiza) is drawn to a liposome for delivering a biologically active antifolate, as of Niyikiza, title and abstract. Said antifolate may be raltitrexed (spelled incorrectly as “ralitrexed”), as of at least page 5, first full paragraph of Niyikiza. Nevertheless, Niyikiza differs from the claimed invention at least because:
“Regular” raltitrexed is mono-glutamated, which differs from the claimed gamma polyglutamated raltitrexed
The liposome described by the abstract if Niyikiza has a targeting moiety, which is excluded by the instant claims; and
There is no evidence that the liposome of Niyikiza would have been capable of direct delivery of active agent into cells, especially if the liposome of Niyikiza were to have been modified to have removed the targeting moiety.
As such, the instant claims have not been rejected over Niyikiza.
The examiner further notes here that antifolates capable of being polyglutamated, including raltitrexed (but also including others such as methotrexate or aminopterin), are generally administered as monoglutamates and become gamma polyglutamated in vivo by folylpoly-gamma-glutamate synthetase already found in the human body during normal operation. See the instant specification, page 2, top paragraph.
Nevertheless, gamma polyglutamated raltitrexed that was formed from the in vivo polyglutamation by folylpoly-gamma-glutamate synthetase of administered monoglutamated raltitrexed is insufficient to meet the claimed requirements. This is because the raltitrexed that was polyglutamated in vivo would not have been in a liposome having the recited properties.
As such, Niyikiza’s teaching of “regular” raltitrexed in a liposome with the recited properties does not read on the required polyglutamated raltitrexed even though “regular” raltitrexed becomes polyglutamated in vivo. This is because polyglutamated raltitrexed that became polyglutamated in vivo would not have been in a liposome with the recited properties.
Zeta Potential and Direct Delivery into Cells: The examiner notes that in the case of liposomes and/or other lipid nanoparticles, the presence of cationic charges (resulting in a positive/cationic zeta potential and/or surface charge) are often used to achieve direct delivery of the payload into cells. This delivery strategy was used in the case of the commercially available mRNA COVID-19 vaccines from Moderna and Pfizer/BioNTech, which became commercially available in 2020 during the COVID-19 pandemic. However, this strategy of using positive charge to promote direct delivery into cells would have been known to the skilled artisan prior to the effective filing date of the instant application in 2018.
In support of this position, the examiner cites Schoenmaker et al. (International Journal of Pharmaceutics, 601 (2021), Article 120586, pages 1-13). Schoenmaker et al. (hereafter referred to as Schoenmaker) is a review article explaining the lipid compositions of the commercially available COVID-19 mRNA vaccines and teaches cationic lipids in said vaccine compositions on at least page 8, figure 6. Schoenmaker further explains that cationic lipids are useful to facilitate membrane fusion during internalization, as of Schoenmaker, page 4, left column, first paragraph in section 2.2.
In a similar vein, the examiner also cites Torchilin et al. (US 2005/0163832 A1). Torchilin, as of at least paragraphs 0010 and 0019, provides evidence that the skilled artisan would have known to use positively charged (cationic) lipids in the make-up of the liposome for safe and efficient intracellular delivery of therapeutic agents. As Torchilin was published in 2005, this indicates that the strategy of using positive charges to promote direct delivery into cells was known prior to the effective filing date of the instant application.
In the instantly claimed invention, applicant appears to have achieved direct delivery of the therapeutic agent into cells using liposomes having a neutral or negative zeta potential. This would not have been expected by the skilled artisan, because the skilled artisan would have expected that a positive zeta potential would have been needed in order to have achieved direct delivery of the active agent into a cell. Presence of an unexpected property is evidence of non-obviousness; in this case, the unexpected property is successful delivery of active agent despite lacking the positive surface charge. See MPEP 716.02(a)(III). Omission of an element (the positive zeta potential has been effectively omitted as the claims recite a neutral or negative zeta potential) and retention of the element’s function (the ability to directly deliver the payload to cells wherein the payload is gamma polyglutamated raltitrexed) is an indicium of non-obviousness. See MPEP 2144.04(II)(B).
Also, proceeding contrary to the accepted wisdom in the art is evidence of non-obviousness. See MPEP 2145(X)(D)(3). In this case, the accepted wisdom would be that a positive zeta is needed for direct delivery into a cell. However, applicant achieved direct delivery into a cell with a neutral or negative zeta potential, wherein a neutral or negative zeta potential is by definition not a positive zeta potential. This goes against the accepted wisdom in the art and is thereby evidence of non-obviousness.
Niyikiza 2018 References – Not Prior Art: As relevant art, the examiner cites Niyikiza et al. (WO 2018/031968 A1) and Niyikiza et al. (WO 2018/031980 A1). Both references are drawn to polyglutamated antifolates and teach liposomes. Both references were published on 15 February 2018, which is after the effective filing date of the instant application of 7 February 2018. Both references were also effectively filed earlier than the effective filing date of the instant application.
Nevertheless, both references have the same inventive entity as the instant application. Therefore, both references are not prior art under 35 U.S.C. 102(a)(2) despite the earlier filing date; this is because of the AIA 35 U.S.C. 102(b)(2)(A) exception.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ISAAC SHOMER whose telephone number is (571)270-7671. The examiner can normally be reached 7:30 AM to 5:00 PM Monday Through Friday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana Kaup can be reached at (571)272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612
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