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.
Information Disclosure Statement
An information disclosure statement (IDS) was submitted on 13 January 2025. The IDS has been considered. Nevertheless, various non-patent literature references have been crossed out because no reference date has been provided. See MPEP 609.04(a), which indicates that a reference date must be provided for all references listed on the IDS.
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
Claim 95 requires that the liposome is capable of delivering the alpha polyglutamated lometrexol directly into a cell. The examiner understands the term “directly” to require that the alpha polyglutamated lometrexol goes directly from being present in the liposome to being present in a cell, without there being an intermediate state of the alpha polyglutamated lometrexol being present in neither the liposome nor the cell.
Note Regarding Multiple Numerical Ranges in Claims
Various claims recite multiple numerical ranges in the same claim. Independent claim 95 recites this, with a broad range of zeta potential of less than or equal to zero, a narrower range of between 0 to -150 mV, and a narrower example of between -30 to -50 mV. Another 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 does 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.
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 lometrexol. 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 lometrexol 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 notes that common side effects of lometrexol are anemia and leukopenia. See Walling et al. (US 2002/0156023 A1), paragraph 0097.
Leukopenia, which is a lack of white blood cells, results in increased risk of infection, as taught by Ing (Canadian Family Physician, Vol. 30, September 1984, pages 1835-1839), as of the abstract. The skilled artisan would have expected this to have been the case because the function of white blood cells is to fight infection; therefore, a reduced amount of white blood cells results in a reduced ability for the host to fight infection.
Anemia, or at least certain types of anemia, can also result in increased risk of infection. See Hassan et al. (Medicine, Vol. 95:47, 2016, pages 1-5), which teaches the following as of page 1, abstract.
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The above-reproduced text appears to indicate that certain immune functions are deficient in patients with iron deficiency anemia.
As such, the prior art indicates that administration of lometrexol and/or derivatives thereof would have resulted in an increased risk of infection in a significant number of patients due to anemia or leukopenia, 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 lometrexol, or polyglutamated derivatives thereof, 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. Claim 112 does not further limit the type of infection treated.
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 antifolates to treat cancer. See e.g. page 191, paragraph 00412, in which a liposome comprising poyglutamated antifolate kills cancer cells in vitro (though this particular example is drawn to polyglutamated pemetrexed rather than polyglutamated lometrexol). No examples are provided in which polyglutamated lometrexol is used for treatment of an 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 lometrexol, 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 lometrexol 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 112-113 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,246,019. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
Instant claim 95 is drawn to a liposome comprising alpha polyglutamated lometrexol. This liposome has 3-12 glutamyl groups having alpha carboxyl linkages. The liposome is also pegylated, does not contain a targeting moiety, cell penetrating peptide, or mitochondria penetrating peptide. This liposome has a zeta potential that is zero or negative, and is capable of delivering the alpha polyglutamated lometrexol directly into a cell.
Conflicting claim 1 is drawn to a liposome comprising alpha polyglutamated lometrexol. This liposome has either 2-10 or more than 4 glutamyl groups having alpha carboxyl linkages. The liposome is also pegylated, does not contain a targeting moiety, cell penetrating peptide, or mitochondria penetrating peptide. This liposome has a zeta potential that is zero or negative, and is capable of delivering the alpha polyglutamated lometrexol directly into a cell.
The instant and conflicting claims differ because a liposome comprising alpha polyglutamated lometrexol with two glutamyl groups is within the scope of the conflicting claims but not within the scope of the instant claims. Nevertheless, the subject matter of the conflicting claims anticipates that of the instant claims, e.g. in the case wherein there are 4-6 glutamyl groups on the lometrexol. This would have effectively anticipated the claimed invention, thereby resulting in a prima facie case of anticipatory-type non-statutory double patenting.
Claims 95-110 and 112-113 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 and 18-36 of U.S. Patent No. 11,344,628. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
Instant claim 95 is drawn to a liposome comprising alpha polyglutamated lometrexol. This liposome has 3-12 glutamyl groups having alpha carboxyl linkages. The liposome is also pegylated, does not contain a targeting moiety, cell penetrating peptide, or mitochondria penetrating peptide. This liposome has a zeta potential that is zero or negative, and is capable of delivering the alpha polyglutamated lometrexol directly into a cell.
The conflicting claims are drawn to a liposome comprising a polyglutamated antifolate encapsulating by a liposome. The polyglutamate has at least 4 glutamate residues linked by the alpha carboxyl groups, as of conflicting claim 1, and the antifolate may be lometrexol, as of conflicting claim 4. The liposome lacks a targeting moiety, as of conflicting claim 1, and is pegylated, as of conflicting claim 8. The liposome of conflicting claim 16 is neutral or negatively charged, and would consequently have been expected to have lacked a cell penetrating peptide or mitochondria penetrating peptide.
The instant and conflicting claims differ because the instant claims require that the liposome is capable of delivering the payload directly into a cell. This is not recited by the conflicting claims. Nevertheless, the liposome of the conflicting claims appears to comprise all of the elements required by the instant claims. As such, there would have been a reasonable expectation that the liposome of the conflicting claims would have been capable of delivering the alpha polyglutamated lometrexol directly into the cell, even if that was not recognized by the conflicting claims.
Claims 95-110 and 112-113 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 and 20-27 of U.S. Patent No. 12,296,022. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
Instant claim 95 is drawn to a liposome comprising alpha polyglutamated lometrexol. This liposome has 3-12 glutamyl groups having alpha carboxyl linkages. The liposome is also pegylated, does not contain a targeting moiety, cell penetrating peptide, or mitochondria penetrating peptide. This liposome has a zeta potential that is zero or negative, and is capable of delivering the alpha polyglutamated lometrexol directly into a cell.
The conflicting claims are drawn to a liposome comprising a polyglutamated antifolate encapsulating by a liposome. The polyglutamate antifolate may be polyglutamated lometrexol, as of conflicting claim 4, and there may be 4-6 glutamyl groups, as of conflicting claims 2-3. The liposome lacks a targeting moiety, as of conflicting claim 1. The liposome of conflicting claim 18 is neutral or negatively charged, and would consequently have been expected to have lacked a cell penetrating peptide or mitochondria penetrating peptide.
The instant and conflicting claims differ because the instant claims require that the liposome is capable of delivering the payload directly into a cell. This is not recited by the conflicting claims. Nevertheless, the liposome of the conflicting claims appears to comprise all of the elements required by the instant claims. As such, there would have been a reasonable expectation that the liposome of the conflicting claims would have been capable of delivering the alpha polyglutamated lometrexol directly into the cell, even if that was not recognized by the conflicting claims.
The instant and conflicting claims also differ because the instant claims require alpha polyglutamated lometrexol. In contrast, the conflicting claims recite polyglutamated lometrexol, but do not specify whether the lometrexol is alpha polyglutamated or gamma polyglutamated. Nevertheless, the examiner understands the polyglutamated lometrexol of the conflicting claims to read on both alpha and gamma polyglutamated lometrexol. In view of this, the examiner understands the conflicting claims to recite alpha polyglutamated lometrexol, which is the same material as recited by the instant claims.
Claims 95-110 and 112-113 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 6, 9-10, 17-20, 30, 32, 40, 52, 55, 69, 72-73, 80-81, 83-84, 92-93 and 96 of copending Application No. 18/755,082 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
Instant claim 95 is drawn to a liposome comprising alpha polyglutamated lometrexol. This liposome has 3-12 glutamyl groups having alpha carboxyl linkages. The liposome is also pegylated, does not contain a targeting moiety, cell penetrating peptide, or mitochondria penetrating peptide. This liposome has a zeta potential that is zero or negative, and is capable of delivering the alpha polyglutamated lometrexol directly into a cell.
Copending claim 1 is drawn to a liposome having a polyglutamated antifolate encapsulated by a pegylated liposome. The polyglutamted antifolate has at least two glutamyl groups via alpha carbon linkages, as of copending claim 1, and between 4-6 such groups as of copending claim 9. The antifolate may be lometrexol, as of copending claim 3. The liposome has a zeta potential that is either negative or zero, as of copending claim 40, which would appear to indicate the lack of a cell penetrating peptide or mitochondria penetrating peptide. The liposome does not comprise a targeting moiety, as of copending claim 52.
The instant and copending claims differ because the instant claims require that the liposome is capable of delivering the payload directly into a cell. This is not recited by the conflicting claims. Nevertheless, the liposome of the copending claims appears to comprise all of the elements required by the instant claims. As such, there would have been a reasonable expectation that the liposome of the conflicting claims would have been capable of delivering the alpha polyglutamated lometrexol directly into the cell, even if that was not recognized 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 112-113 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 15, 17, 22, 25-26, 36, 52-53, 57-60, 65-66, and 69 of copending Application No. 18/902,040 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
Instant claim 95 is drawn to a liposome comprising alpha polyglutamated lometrexol. This liposome has 3-12 glutamyl groups having alpha carboxyl linkages. The liposome is also pegylated, does not contain a targeting moiety, cell penetrating peptide, or mitochondria penetrating peptide. This liposome has a zeta potential that is zero or negative, and is capable of delivering the alpha polyglutamated lometrexol directly into a cell.
Copending claims 1 and 4 are drawn to a liposome encapsulating polyglutamated lometrexol wherein the liposome is pegylated and does not comprise a targeting moiety. Copending claims 2-3 recite five or six glutamyl groups. Copending claim 25 recites a zeta potential that is zero or negative.
The instant and copending claims differ because the instant claims require that the liposome is capable of delivering the payload directly into a cell. This is not recited by the conflicting claims. Nevertheless, the liposome of the copending claims appears to comprise all of the elements required by the instant claims. As such, there would have been a reasonable expectation that the liposome of the conflicting claims would have been capable of delivering the alpha polyglutamated lometrexol directly into the cell, even if that was not recognized by the copending claims.
The instant and copending claims also differ because the instant claims require alpha polyglutamated lometrexol. In contrast, the copending claims recite polyglutamated lometrexol, but do not specify whether the lometrexol is alpha polyglutamated or gamma polyglutamated. Nevertheless, the examiner understands the polyglutamated lometrexol of the copending claims to read on both alpha and gamma polyglutamated lometrexol. In view of this, the examiner understands the copending claims to recite alpha polyglutamated lometrexol, which is the same material as recited by the instant 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, 76-89, and 91-94 of copending Application No. 19/069,794 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
Instant claim 95 is drawn to a liposome comprising alpha polyglutamated lometrexol. This liposome has 3-12 glutamyl groups having alpha carboxyl linkages. The liposome is also pegylated, does not contain a targeting moiety, cell penetrating peptide, or mitochondria penetrating peptide. This liposome has a zeta potential that is zero or negative, and is capable of delivering the alpha polyglutamated lometrexol directly into a cell.
The copending claims are drawn to a method of administering a liposome comprising a polyglutamated antifolate to treat a disease, as of copending claim 1. The liposome is pegylated and lacks a targeting moiety, and the antifolate has 3-10 D-glutamyl groups, as of copending claim 1. The antifolate may be polyglutamated lometrexol, as of copending claim 83. The liposome may be anionic or neutral, as of copending claim 89, indicating that there is no cell or mitochondria penetrating peptide.
The instant and copending claims differ because the copending claims are drawn to a method, whereas the instant claims are drawn to a composition. Nevertheless, the composition administered by the method of the copending claims appears to have all of the features required by the instant claims.
The instant and copending claims differ because the instant claims require that the liposome is capable of delivering the payload directly into a cell. This is not recited by the conflicting claims. Nevertheless, the liposome of the copending claims appears to comprise all of the elements required by the instant claims. As such, there would have been a reasonable expectation that the liposome of the conflicting claims would have been capable of delivering the alpha polyglutamated lometrexol directly into the cell, even if that was not recognized by the copending claims.
The instant and copending claims also differ because the instant claims require alpha polyglutamated lometrexol. In contrast, the copending claims recite polyglutamated lometrexol, but do not specify whether the lometrexol is alpha polyglutamated or gamma polyglutamated. Nevertheless, the examiner understands the polyglutamated lometrexol of the copending claims to read on both alpha and gamma polyglutamated lometrexol. In view of this, the examiner understands the copending claims to recite alpha polyglutamated lometrexol, which is the same material as recited by the instant 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 6 November 2024 in parent application 16/967,538.
Barenholz Reference – Overview: As relevant prior art, the examiner cites Barenholz (Journal of Controlled Release 160 (2012), pages 117–134), which has been previously cited in the file record. 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 alpha polyglutamated lometrexol 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 alpha polyglutamated lometrexol 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 alpha polyglutamated lometrexol 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).
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.
In applicant’s response in parent application 16/967,538 on 15 April 2024, applicant appears to argue that the prior art composition is not capable of direct delivery to cells. See at least page 9, top paragraph of applicant’s response on 15 April 2024 in parent application 16/967,538. To the extent that the above-reproduced text accurately describes what the skilled artisan would have expected regarding alpha polyglutamated lometrexol at the time of filing, 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 alpha polyglutamated lometrexol would have behaved more similarly to cisplatin as compared with doxorubicin. Therefore, the skilled artisan would not have expected a benefit for administering alpha polyglutamated lometrexol 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 alpha polyglutamated lometrexol via liposome.
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 alpha polyglutamated lometrexol via liposome. However, applicant appears to have administered alpha polyglutamated lometrexol via 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), which has been previously cited in the file record. 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 lometrexol, as of at least page 5, first full paragraph of Niyikiza. Nevertheless, Niyikiza differs from the claimed invention at least because:
“Regular” lometrexol is mono-glutamated, which differs from the claimed polyglutamated lometrexol
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.
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 zeta potential) are often used to achieve direct delivery of the payload into cells. In fact, 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 while having a neutral or negative zeta potential, which differs from the cationic zeta potential taught by Torchilin and Schoenmaker. 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 delivery the payload to cells wherein the payload is alpha polyglutamated lometrexol) 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.
Relevant Patents – No Double Patenting
US Patent 12,076,402: As a relevant document, the examiner cites US Patent 12,076,402. The ‘402 patent has common inventors with the instant application. Nevertheless, the examiner has decided not to write a double patenting rejection over the claims of this patent for the following reasons.
The instant claims require a liposome which comprises alpha polyglutamated. Crucially, this liposome must be pegylated but must lack a targeting ligand, lack a positive zeta potential, and must lack a cell or mitochondria penetrating peptide, and must be able to deliver the alpha polyglutamated lometrexol directly to a cell.
The claims of the ‘402 patent are drawn to a liposome which may comprise alpha polyglutamated lometrexol. These claims do not appear to specifically recite a liposome lacking a targeting ligand. In fact, various dependent claims of the ‘402 patent positively recite the presence of a targeting ligand, such as claims 26-31. The claims of the ‘402 also patent do not recite that the composition would have been capable of delivering its payload directly into a cell, as required by the instant claims. There would have been no expectation that the composition recited by the claims of the ‘402 patent would have been capable of delivering its payload directly into a cell in the absence of a targeting ligand or cell penetrating peptide. The fact that a certain result or characteristic may occur or be present in the prior art is not sufficient to establish the inherency of that result or characteristic. See MPEP 2112(IV).
US Patent 11,771,700: As a relevant document, the examiner cites US Patent 11,771,700. The ‘700 patent has common inventors with the instant application. Nevertheless, the examiner has decided not to write a double patenting rejection over the claims of this patent for the following reasons.
Instant claim 95 is drawn to a liposome comprising alpha polyglutamated lometrexol.
Claim 1 of the ‘700 patent is drawn to a liposomal gamma polyglutamated lometrexol.
The examiner has decided not to reject the instant claims over the claims of the ‘700 patent on the grounds of double patenting. This is because in the instant claims, the lometrexol is alpha polyglutamated. In contrast, in the subject matter claimed by the ’700 patent, the lometrexol is gamma polyglutamated. These entail different polyglutamation at different points in the molecule. As best understood by the examiner, gamma polyglutamation of both folate and antifolates like lometrexol occurs naturally to a much greater degree than alpha polyglutamation. See e.g. Sakamoto et al. (Biochemical and Biophysical Research Communications, Vol. 365, 2008, pages 801-807). Sakamoto teaches the presence of γ-glutamyl hydrolase (GGH). This which would have been expected to have hydrolyzed lometrexol γ-polyglutamate, as recited by the claims of the ‘542 application, but not lometrexol α-polyglutamate, as recited by the instant claims.
As such, the skilled artisan would have expected significantly different degradation profiles between the claimed α-substituted lometrexol and the γ-substituted lometrexol of the ‘700 patent due to the existence and prevalence of γ-glutamyl hydrolase (GGH). Therefore, the skilled artisan would not have expected these compounds to have been obvious over one another and there would have been no expectation that these compounds would have had similar properties.
The examiner takes the position that the rationale applied above also relates to other issued patents and copending cases whose claims are entirely drawn to γ-polyglutamated lometrexol rather than the claimed α-polyglutmated lometrexol.
US Patent 11,534,498: No double patenting rejection over the claims of US Patent 11,534,498 has been written for essentially the same reason that no double patenting rejection over the claims of US Patent 11,771,700 was written. Namely, the claims of the ‘498 patent are drawn to a liposome encapsulating gamma polyglutamated lometrexol, whereas the instant claims are drawn to a liposome encapsulating alpha polyglutamated lometrexol.
Conclusion
No claim is allowed.
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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612
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