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 .
Claim Status
Claims 1-2, 4-10, 16-25 are pending.
Claims 3 and 11-15 have been canceled.
Claim 19 is withdrawn.
Claims 1-2, 5, 7, 9-10, 16, 18-19 and 21 are currently amended.
Claims 22-25 have been added.
Claims 1-2, 4-10, 16-18 and 20-25 are currently under consideration.
Claims 1-2, 4-10, 16-18 and 20-25 are rejected.
Acknowledgement of Receipt
This Office Action is in response to the Applicants’ amendments and remarks filed 09/21/2025.
Withdrawn Objections/Rejections
The objections to claims 1 and 18 are withdrawn.
In light of the new amendments and/or upon further consideration, the rejection of claims 1-2 and 21 under 35 U.S.C. § 112(b) as being indefinite are withdrawn.
In light of the new amendments and/or upon further consideration, the rejection of claims 1, 4, 6, 8-10, 16-18 and 21 under 35 U.S.C. § 102 as being anticipated by Erler, evidenced by Martin are withdrawn.
New Objections and Rejections
Applicants’ amendments have necessitated the following grounds of rejection:
Claim Objections
Applicants’ amendments have necessitated the following objections:
Claim 21 is objected to because of the following informalities: “an immunotherapeutic agent,” is recited twice, first in line 4 and then in the last line of claim 21.
Claim 23 is objected to because of the following informalities: the last term in line 4 of claim 23 recites “-succynil).” This appears to be a misspelling of the term succinyl.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 (a) are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicants are advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4-5, 8-10, 16-18, 20-23 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Erler (US 2007/0225242, cited on IDS) in view of Accardo (US 2017/0209474 A1, pub. 07/27/2017).
Erler discloses the modulation of lysyl oxidase (LOX) expression to inhibit or reduce tumor growth by utilizing an effective amount of an inhibitor of lysyl oxidase activity and a pharmaceutically acceptable carrier ([0022], claim 1). Erler teaches anti-LOX antibody ([0115], [0120]) to target immune system cells to unwanted cells and may be prepared using known synthetic protein chemistry methods involving crosslinking agents, for example, immunotoxins via disulfide exchange reaction or by forming a thioether bond ([0129]). The anti-LOX antibody may be conjugated to a cytotoxic agent such as a chemotherapeutic agent ([0131]). Erler teaches that conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP) ([0132]). The anti-LOX antibodies disclosed by Erler may be formulated as immunoliposomes; liposomes containing the antibody ([0134]). Erler clearly meets the lipid, cholesterol, an anti-lysl (LOX) antibody and therapeutic agent requirements of instant claim 1 in paragraphs [0135]-[0136] below.
“Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and poly(ethylene glycol)-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Fab' fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al., J. Biol. Chem., 257: 286 288 (1982) via a disulfide-interchange reaction. A chemotherapeutic agent (Such as doxorubicin) is optionally contained within the liposome,” ([0135]).
“Liposomes can also be used to deliver the anti-LOX antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target LOX protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target LOX protein sequence. Alternatively, or in addition, the composition may comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. The active ingredients may also be entrapped in microcapsules prepared, for example, in colloidal drug delivery systems (for example, liposomes),” ([0136]).
Erler does not teach succinyl-functionalized PEG.
Accardo discloses the obtainment, by using a kit, of liposomal doxorubicin in which liposomes are externally modified with a targeting peptide able to drive liposomal doxorubicin in a selective way on membrane receptors over-expressed in tumors ([0002], claim 1). Accardo discloses a liposomal doxorubicin drug that is combined with a modified phospholipid with a reactive function for example, DSPE-PEG-maleimide, with a peptide modified with an appropriate reactive function (abstract, [0036], claim 5).
Accardo teaches that the modified phospholipid is preferably a DSPE-PEG2000 (N-(polyethylene glycol 2000)-1, 2-diasteroyl-sn-glycero-3-phosphoethanolamine) derivative modified with the introduction of reactive functions such as succinyl groups ([0058]). Accardo teaches DSPE PEG(2000)-Succinyl ([0066], claim 2) and that DSPE-PEG(2000) = N-(carbonyl-methoxypolyethylene glycol 2000)-1,2 distearoyl-sn-glycero-3-phosphoethanolamine ([0067]).
It would have been prima facie obvious to a person of ordinary skill in the art, ahead of the effective filing date of the claimed invention, to utilize the PEG-succinyl taught by Accardo in the teachings of Erler with expected results. One would be motivated to do so with a reasonable expectation of success because Accardo provides a liposomal formulation to obtain a peptide modified doxorubicin liposomal drug that is easy for clinicians to perform just before the clinical use of the final product ([0035-0036]). The combining the of the doxorubicin containing liposome of Erler with the modified doxorubicin liposomes taught by Accardo would contribute to the improvement of selectivity based on the over-expression of the targeting receptors to suggest improvements in patient safety and overall treatment outcomes, absent a clear showing of evidence to the contrary.
Regarding claim 2, Erler teaches liposomes with a lipid comprising PEG ([0135]).
Regarding claims 4-5 and 21, in addition to teaching the antitumor antibiotic doxorubicin ([0072], [0135]), Erler teaches epirubicin as an exemplary cytotoxic agent ([0146]). Here the prior art makes obvious to employ epirubicin given that doxorubicin and epirubicin are obvious variants.
Regarding claim 8, Erler teaches that the compositions further include pharmaceutically acceptable materials, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, i.e., carriers ([0149], [0158]). Erler teaches the formulation and delivery methods are adapted according to the site and the disease to be treated ([0151]).
Claims 9-10 and 16-18 are intended use claims and a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. The cited prior art teaches the elements of the structure and therefore obvious that the capability of performing the intended use would have been met.
Regarding claim 20, Erler teaches formulations suitable for parenteral administration, e.g., intravenous, including formulations encapsulated in liposomes ([0151]). In addition, Erler intravenously injects MDA231 human breast cancer cells that expressed LOX-targeting shRNA ([0222-0223], [0242], [0248]).
Regarding claim 22, Accardo teaches liposomes comprising DSPE-PEG-2000 ([0058]).
Regarding claim 23 (i.e., mixture of DSPE-PEG-2000 and DSPE-(2000)-succynil [sic]), as mentioned above, Erler discloses SPDP ([0132]), known in the art as the activating agent to functionalize DSPE-PEG derivatives (specifically DSPE-PEG-amine) to introduce a reactive disulfide group. Nevertheless, Erler does not explicitly teach DSPE.
Accardo explicitly teaches DSPE-PEG(2000) ([0058], [0067]) and DSPE PEG(2000)-Succinyl ([0066], claim 2). It would have been obvious to a skilled artisan to obtain a mixture of these because by combining stealth properties (long circulation, reduced protein binding) of standard PEG with the reactive carboxyl group on the succinyl lipid for attaching targeting ligands (like antibodies or peptides), would achieve improved controlled drug targeting. Accardo builds on the modulation of LOX expression taught by Erler by obtaining a final product, liposomal therapeutic, modified to achieve targeting in a selective way (Accardo, title, [0112])
Regarding claim 25 (i.e., lipid comprising the succinyl-functionalized PEG moiety, the Examiner notes that the species recited in the last line of claim 25 mirrors species 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[succinyl(polyethylene glycol)-2000] in claim 23. As such, the DSPE PEG(2000)-succinyl disclosed by Accardo ([0066], claim 2) reads on the claim.
Claims 6-7 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Erler and Accardo as applied to claims 1-2, 4-5, 8-10, 16-18 and 20-23 and 25 above, further in view of Martin (J. Bio. Chem., Vol. 257, No. 1, pp. 286-288).
The teachings of Erler and Accardo above are incorporated herein.
Regarding claim 6 (i.e., 150 to 250 nm), Applicants disclose “Average diameter (Z Average)” (see Spec., pg. 27, line 31). Erler, supra paragraph [0135], the liposomes obtained a desired diameter. Martin, cited by Erler, further teaches the diameter of the liposome is 0.2 µm diameter (i.e., 200 nm) (see Martin, pg. 287, col. 2, para. 1; pg. 288, col. 1, para. 1) to fall within the claimed range of 150 to 250 nm. MPEP 2144.05 states that a prima facie case of obviousness exists in the case where the claimed ranges overlap or lie inside ranges disclosed by the prior art.
Regarding claims 7 (i.e., 1:300 - 1:500) and 24 (i.e., 1:500), Applicants disclose ratio in the instant specification in lines 19-20 on page 17 and in Figure 6 (Spec., pg. 24, lines 26-28). Erler teaches liposomes that contain the anti-LOX are prepared according to Martin ([0135]). Martin provides ratios of 70 ± 15, 330 ± 20, and 584 ± 40 µg of Fab'/µmol of vesicle phospholipid, respectively, and suggests an optimal initial concentration range for Fab’ (pg. 287, bridging col. 1-2).
Evidence from Martin establishes prima facie obviousness of the claimed ratios from between about 1:300 to about 1:500 in instant claim 7 and 1:500 in instant claim 24. It would be obvious for a person of ordinary skill in the art to preferably prepare ratio of anti-LOX antibody: PEG-lipid to effectively and efficiently deliver the therapeutic agent (i.e., chemotherapy agent) through routine optimization and experimentation. MPEP 2144.05(II.)(A.) states that differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation."
It would have been prima facie obvious to a person of ordinary skill in the art, ahead of the effective filing date of the claimed invention, to combine the teachings of Erler and Martin with expected results. One would be motivated to do so with a reasonable expectation of success because Erler shows how LOX is a good therapeutic target for the prevention of metastasis in breast cancer, and suggest a mechanism for preventing early and late stages of metastasis ([0254-0257]). While Erler provides examples ([0176] Example 1; [0182] Example 5), Martin teaches that optimization of the carrier properties and targeting potential of liposomes improves upon the art, absent evidence to the contrary.
Response to Arguments
35 U.S.C. § 103 – claim 1 in view of Martin
Applicants’ arguments have been fully considered but they are not persuasive.
Applicants argue that Erler's and Martin's use of di-sulfide bonds for conjugating an antibody to a liposome: i) Lacks site specificity, leading to random orientation of the antigen- binding site, ii) Is unstable under reducing biological conditions, and, iii) Is prone to early antibody detachment in vivo.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., exclusion of disulfide bonds) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In response to applicant's argument that use of a (see Remarks, pg. 13, para. 1-2), the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
35 U.S.C. § 103 – claim 2-3 in view of Manjappa
Applicants argue that Manjappa does not teach the limitation (added by the instant amendment): “wherein the anti-LOX antibody is conjugated to a lipid by a succinyl-functionalized PEG moiety” and that one of skill after reading Manjappa would not have been motivated to modify Erler to teach this method (see Remarks, pg. 14, para. 3-4).
Manjappa is no longer relied upon.
For these reasons, Applicants’ arguments are found unpersuasive.
Conclusion
All claims under consideration remain rejected; no claims are 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 extension fee 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Karen Ketcham whose telephone number is (571)270-5896. The examiner can normally be reached 900-500 ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at 571-272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Karen Ketcham/Examiner, Art Unit 1614
/ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614