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
Applicant’s amendments and remarks, filed 08/25/2023, are acknowledged.
Claims 1, 2, 4, and 21 are amended.
Claims 1-25 are pending.
DETAILED ACTION
Election/Restrictions
Applicant’s group election without traverse of Group I, claims 1-23, drawn to an immunoconjugate or drug-linker in the reply filed on 01/15/2026 is acknowledged.
Applicant’s species election without traverse of Formula 3 (for the acid-sensitive linker) and Sacituzumab (for the antibody or antigen-binding site) in the reply filed on 01/15/2026 is acknowledged.
Claims 24 and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/15/2026.
As such, claims 1-23 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/14/2023, 06/18/2024, 10/08/2024, and 05/30/2025 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Drawings
The drawings are objected to because FIG. 4 recites “SN38” which should read “SN-38”.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
Page 3: “Valine-Citrulllin” should read “Valine-Citrulline”.
Page 6: “cetumximab” should read “cetuximab”.
Page 7: “cextuximab” should read “cetuximab”.
Page 14: “Top 1” should read “Top1”.
Page 20: “… side effects such weight loss” should read “… side effects, such as weight loss,”.
Page 50: “FL118-liker 2 conjugate” should read “FL118-linker 2 conjugate”.
Table 15: The last column is not translated.
Appropriate correction is required.
The use of the term Genentech, Seattle Genetics, Mylotarg, Kadcyla, Immunomedics, Daiichi-Sankyo, Trodelvy, Enhertu, Adcetris, Padcev, Polivy, Gibco, HyClone, Promega, CellTiter-Glo, Envision, PerkinElmer, and GraphPad Prism, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1, 5, 7, 13, and 23 are objected to because of the following informalities:
Claim 1: “wherein FL118 drug of Formula 1” should read “wherein the FL118 drug of Formula 1”.
Claim 1: remove the comma after “efflux pump”.
Claim 5: “…binds to a receptor on cell surface” should read “…binds to a receptor on the cell surface of said cancer cells”.
Claim 7: “which is one of human epidermal growth factor receptor (HER/EGFR/ERBB)” should be removed.
Claim 7: “HER2”, “FolR”, “PSMA”, “Trop-2”, “HER”, “EGFR”, and “ERBB” are acronyms and/or abbreviations which should be spelled out on first occurrence.
Claim 13: “cancel cell” should read “cancer cell”.
Claim 23: “trastzumab” should read “trastuzumab”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 2 recite “an antigen-binding site that targets an antigen of cancer cells”. It is unclear if this antigen-binding site is in reference to the antibody or antigen-binding site-containing fragment thereof of the immunoconjugate, or if it is a completely different antigen-binding site.
Claims 1 and 22 recite “wherein at least one FL118 drug” or similar language which indicates more than one FL118 drug in the claimed immunoconjugate. However, claim 1 only indicates there is one FL118 drug in the immunoconjugate (i.e., “an FL118 drug of Formula 1”); thus it is unclear whether the immunoconjugate only comprises one FL118 drug, or there are multiple FL118 drugs. As such, claims 1, 22, and their dependent claims are rejected.
Claims 1, 2, and 21 recite “(pH ≤ 7)” within parentheticals. It is not clear if the language recited in the parentheses is limiting, or if it is only exemplary (i.e., the claims recite an “acidic environment”, but a pH of 7 is considered more neutral than acidic, therefore it is unclear whether a pH 7 is encompassed in the claim).
The term “small number” in claim 6 is a relative term which renders the claim indefinite. The term “small number” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The claims nor the specification provide a definition for one to understand what the term encompasses or what is considered a “small number” without a standard value to compare; thus, one would not be apprised of the scope of the invention.
Claim 7 recites “which is one of human epidermal growth factor receptor”. It is unclear if this phrase is in reference to Trop-2, or if it is for any of the antigens previously recited.
Further, claim 7 recites “HER/EGFR/ERBB” within parentheticals. It is not clear if the language recited in the parentheses is limiting, or if it is only exemplary (i.e., only HER, EGFR, or ERBB, and not any of the previously recited antigens).
Claims 11 and 20 recite “wherein n is each independently an integer from 5 to 9” within parentheticals. It is not clear if the language recited in the parentheses is limiting, or if it is only exemplary.
Claim 16 recites “wherein, X1 and X2 are each independently -H or -halogen; Y is -NH-, -NRA -, or null; … and n is an integer from 5 to 9 ” within parentheticals. It is not clear if the language recited in the parentheses is limiting, or if it is only exemplary (i.e., are the elements of Formula 2 limited to those recited in parentheticals, or if any modifications can be made).
Claim 22 recites the limitation "a drug-linker conjugate or a pharmaceutically acceptable salt thereof according to claim 1" in part (a). There is insufficient antecedent basis for this limitation in the claim. Specifically, claim 1 does not recite “a drug-linker conjugate”.
Further, claim 22 recites “the acid-sensitive linker of Formula 2”. This limitation incorporates a relative term in the claim. While the specification and claims define what Formula 2 encompasses, MPEP 2173.05(s) states that wherein possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). As such, claim 22 and its dependent claims are rejected.
Claim Rejections - 35 USC § 112(a) Written Description
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.
Claims 1-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is drawn to an immunoconjugate comprising: [an FL1 18 drug of Formula 1] -[an acid-sensitive linker] -[an antibody or antigen-binding site-containing fragment thereof]; or a pharmaceutically acceptable salt thereof, wherein at least one FL118 drug of Formula 1 is linked to an antibody or antigen-binding site-containing fragment thereof through an acid-sensitive linker, wherein after being targeted to cancer cells by an antigen-binding site that targets an antigen of cancer cells, the acid-sensitive linker is degraded in acidic environment around cancer (pH ≤ 7) to free at least a part of the FL118 drug of Formula 1 and the free FL118 drug of Formula 1 penetrates a cell membrane and moves into the cells, wherein FL118 drug of Formula 1 inhibits the action of an efflux pump, to enrich the intracellular free FL1 18 drug of Formula 1, and optionally, wherein the immunoconjugate in which the FL1 18 drug of Formula 1 is linked is internalized into the cell to free the FL118 drug of Formula 1 at lysosomes.
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Claim 2 is drawn to the immunoconjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein after being targeted to cancer cells by an antigen-binding site that targets an antigen of cancer cells, the acid-sensitive linker is degraded in acidic environment around cancer (pH ≤ 7) to free at least a part of the FL118 drug of Formula 1 and free FL118 drug of Formula 1 penetrates a cell membrane and moves into the cells while penetrating infiltrating deep into the cancer tissue.
Claim 3 is drawn to the immunoconjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein, for the free FL118 drug of Formula 1 to be released when the acid-sensitive linker is degraded, the FL118 drug of Formula 1 is linked with the acid-sensitive linker by a carbonate or ester bond.
Claim 4 is drawn to the immunoconjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the cells into which the free FL118 drug of Formula 1 moves are targeted cancer cells and/or surrounding cells thereof.
Claim 5 is drawn to the immunoconjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the antibody or antigen-binding site thereof binds to a receptor on cell surface.
Claim 6 is drawn to the immunoconjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the antibody or antigen-binding site thereof targets antigens selectively distributed on the surface of cancer or cancer cell overexpression antigens, which are also distributed in a small number in normal tissues.
Claim 7 is drawn to the immunoconjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the antibody or antigen-binding site thereof targets HER2, FolR, PSMA or Trop-2, which is one of human epidermal growth factor receptor (HER/EGFR/ERBB).
Claim 8 is drawn to the immunoconjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the acid-sensitive linker is derived from a compound of Formula 2 below.
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Claim 9 is drawn to the immunoconjugate or a pharmaceutically acceptable salt thereof according to claim 8, wherein in Formula 2 above, wherein X1 and X2 are each independently -H or -halogen; Y is -NRA -, or null; Z is -C1-C4 alkyl-, -(C1-C2 alkyl)-(C3-C6 cycloalkyl)- or -(C3-C6 cycloalkyl)-(C1- C2 alkyl)-; W is -RB-,-M-RB-M-, -M-RB- or -RB-M-Rc-;
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Claim 10 is drawn to the immunoconjugate or a pharmaceutically acceptable salt thereof according to claim 8, wherein an alcohol group site of the FL118 drug of Formula 1 and an alcohol group site of the acid-sensitive linker of Formula 2 are linked.
Claim 11 is drawn to the immunoconjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the [FL118 drug of Formula 1]-[acid-sensitive linker] conjugate is derived from any one selected from the group consisting of compounds represented by Formulas 3 to 5 below.
[Formula 3]
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Claim 12 is drawn to the immunoconjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the [acid-sensitive linker]-[antibody or antigen-binding site- containing fragment thereof] link is formed as a thiol group contained in the antibody or antigen- binding fragment thereof is bonded to a maleimide group or a maleic hydrazide group of the acid-sensitive linker.
Claim 13 is drawn to the immunoconjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the antibody or antigen-binding site-containing fragment thereof can target a cancel cell having resistance to SN-38 drug of Formula 6 below:
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Claim 14 is drawn to the immunoconjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the immunoconjugate has an average drug-to-antibody ratio (DAR) of 2 to 12.
Claim 15 is drawn to a pharmaceutical composition for preventing or treating cancer, comprising an immunoconjugate or pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.
Claim 16 is drawn to a drug-linker conjugate or a pharmaceutically acceptable salt thereof, wherein FL118 drug of Formula 1 below is linked to an acid-sensitive linker of Formula 2 below.
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Claim 17 is drawn to the drug-linker conjugate or a pharmaceutically acceptable salt thereof according to claim 16, wherein in Formula 2 above, X1 and X2 are each independently -H or -halogen; Y is -NRA -, or null; Z is -C1-C4 alkyl-, -(C1-C2 alkyl)-(C3-C6 cycloalkyl)- or -(C3-C6 cycloalkyl)-(C1- C2 alkyl)-; W is -RB-,-M-RB-M-, -M-RB- or -RB-M-Rc-;
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Claim 18 is drawn to the drug-linker conjugate or a pharmaceutically acceptable salt thereof according to claim 16, wherein for the free FL118 drug of Formula 1 to be released when the acid-sensitive linker is degraded, the FL118 drug of Formula 1 is linked with the acid- sensitive linker by a carbonate or ester bond.
Claim 19 is drawn to the drug-linker conjugate or a pharmaceutically acceptable salt thereof according to claim 16, wherein an alcohol group site of the FL118 drug of Formula 1 and an alcohol group site of the acid-sensitive linker of Formula 2 are linked.
Claim 20 is drawn to the drug-linker conjugate or a pharmaceutically acceptable salt thereof according to claim 16, wherein the drug-linker conjugate is any one selected from the group consisting of compounds represented by Formulas 3 to 5 below.
[Formula 3]
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Claim 21 is drawn to the drug-linker conjugate or a pharmaceutically acceptable salt thereof according to claim 16, wherein the acid-sensitive linker of Formula 2 is degraded in acidic environment (pH ≤ 7) to free the FL118 drug of Formula 1.
Claim 22 is drawn to an immunoconjugate or pharmaceutically acceptable salt thereof comprising: (a) a drug-linker conjugate or a pharmaceutically acceptable salt thereof according to claim 1; and (b) an antibody or antigen-binding site-containing fragment thereof, wherein at least one of the FL118 drugs of Formula 1 is linked to the antibody or antigen- binding site-containing fragment thereof through the acid-sensitive linker of Formula 2.
Claim 23 is drawn to the immunoconjugate or pharmaceutically acceptable salt thereof according to claim 22, wherein the antibody is trastuzumab, cetuximab or sacituzumab.
The specification discloses that FL118 drug of Formula 1 is a strong topoisomerase I inhibitor and has the same camptothecin moiety structure such as SN-38, topotecan, exatecan, etc., which are existing commercially available Top1 inhibitors (see page 12; Fig. 1). FL118 drug has a Top1 inhibitory efficacy that is equivalent to or higher than that of SN-38 in cancer cells, and exhibits 5 to 20 times more powerful cytotoxicity than that of SN-38 in various cancer cell lines (see pages 12-13; Fig. 3). Specifically, the specification discloses that the FL118 drug showed strong tumor regression efficacy compared to SN-38 in colorectal cancer, head and neck cancer, and pancreatic cancer (see page 14). FL118 drug can overcome various resistance mechanisms of SN-38/exatecan such as ABCG2 Transporter (see page 13). When FL118 drug alone is administered systemically, it is rapidly metabolized/released from the blood circulation and shows only a low concentration, but it is rapidly accumulated in cancer tissues immediately after the administration and maintains a high concentration for a long time (see page 13).
The specification also discloses that a carbamate bond provides a better drug linker stability compared to ester and carbonate bonds; however, an unstable ester or carbonate bond is employed instead of a carbamate bond so that the linker can be designed such that the FL118 drug is separable from the drug linker in both outside and inside the cells surrounding the cancer cells in acidic environment (see pages 19 and 20).
Additionally, the specification evaluates the cytotoxicity of the immunoconjugates of Examples 5, 6, 8, and 9, and DS8201 as a control, with the HER2-overexpression JIMT-1 breast cancer cell line, the EGFR-overexpression MDA-MB-468 breast cancer cell line (see Example 11). The immunoconjugates of Examples 5, 6, 8, and 9 exhibited higher cytotoxicity compared to DS8201 (see Figs. 6-12; Tables 4-6 and 9-15). Further, the specification disclose that trastuzumab, cetuximab, or Sacituzumab treatment all showed only partial antitumor effects compared to the saline control group without statistical significance (see page 83).
However, the specification fails to disclose that Applicant was in possession of the large genus of immunoconjugates/drug-linker conjugates as claimed. Specifically, the specification fails to disclose that Applicant was in possession of the large genus of immunoconjugates/drug-linker conjugates comprising any acid-sensitive linker or any antibody/antigen-binding site-containing fragment. Further, the specification fails to disclose that Applicant was in possession of the large genus of Formula 2 as claimed.
Although the specification discloses of trastuzumab-linker-FL118 immunoconjugate (see Examples 5-7), cetuximab-linker-FL118 immunoconjugates (see Example 8), and Sacituzumab-linker-FL118 immunoconjugates (see Example 9), the claims are not limited to these immunoconjugates, and are inclusive of any immunoconjugate comprising FL118 drug, any acid-sensitive linker, and any antibody/antigen-binding site-containing fragment. This indicates that there are hundreds, if not thousands, of possible immunoconjugates encompassed by the claims. Thus, the claims encompass a vast genus of immunoconjugates that have the claimed functions. However, the specification provides limited guidance on the structure and steps required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of immunoconjugates because, inter alia, the specification does not disclose a correlation between the necessary structure of the immunoconjugates and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Although the term antibody does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecule’s function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of immunoconjugates and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of immunoconjugates. The disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163).
The instant claims do not fully describe the structure of the acid-sensitive linker and an antibody or antigen-binding site-containing fragment thereof to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of immunoconjugates, claimed only by a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous immunoconjugates had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of immunoconjugates claimed only by a partial structure and functional characteristic(s). Thus the immunoconjugates described by the instant claims encompasses an overly broad genus, the structure of the acid-sensitive linker and an antibody or antigen-binding site-containing fragment thereof, and the functional outcome.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of immunoconjugates by the functions of the acid-sensitive linker (i.e., degrades in acidic environment around cancer) and the antibody or antigen-binding site (i.e., targets an antigen of cancer cells). As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed immunoconjugates, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Regarding the encompassed antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible antibodies that have specific required functions. In the instant application, neither the art nor the specification provide a sufficient representative number of immunoconjugates or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed immunoconjugates, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed immunoconjugates could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of proteins, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all immunoconjugates.
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed immunoconjugates. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of immunoconjugates as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
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.
Govindan and Ling
Claims 1-23 are rejected under 35 U.S.C. 103 as being unpatentable over Govindan et al (US 2014/0170063 A1, publication date: 06/19/2014), as evidenced by Cardillo et al (Bioconjugate Chem. 2015, 26, 919−931) and further in view of Ling et al (Am J Transl Res 2015;7(10):1765-1781; previously submitted with the Restriction Requirement filed on 11/19/2025).
With respect to instant claims 1-12 and 16-22, Govindan teaches of therapeutic immunoconjugates comprising SN-38 attached to an antibody or antigen-binding antibody fragment (see Abstract). Govindan teaches that the antibodies of use bind to antigens expressed by or otherwise associated with tumor cells such as TROP-2, HER2, and PSMA (see [0010]). Govindan teaches that the immunoconjugates may be efficacious in patients resistant to standard therapies such as irinotecan, the parent agent of SN-38 (see [0023]). Govindan teaches that the preferred conjugation protocol is based on a thiol-maleimide, a thiol-vinylsulfone, a thiol-bromoacetamide, or a thiol-iodoacetamide reaction that is facile at neutral or acidic pH (i.e., pH ≤ 7); thus, obviates the need for higher pH conditions for conjugations (see [0179]). With respect to the linker, Example 6 shows the preparation of CL2A which is a species of instant Formula 2 (see below). Govindan teaches that the CL2A linker comprises a slow-release mechanism which was beneficial for internalizing antibodies penetrating the cell membrane (see [0339]-[0343]).
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Additionally, Table 7 displays the molar substitution ratios (MSR) of several SN-38/Mab conjugates.
With respect to instant claims 14 and 23, Govindan teaches of humanized anti-TROP-2 IgG-SN-38 conjugates (see Example 11) wherein the SN-38 was released from the conjugate primarily by the cleavage at the pH-sensitive benzyl carbonate bond to SN-38’s lactone ring and not he cathepsin B cleavage site (see [0293] and [0307]). Govindan teaches of hRS7-CL2A-SN-38 ADC, wherein the hRS7 is the humanized anti-TROP-2 antibody and has an SMR of 5.8 (see Table 7; Example 11). While Govindan does not recite the name of the hRS7 antibody, it is known in the art that hRS7 is also IMMU-132 or Sacituzumab as evidenced by Cardillo (see Abstract). Further, Cardillo disclose that the hRS7-CL2A-SN-38 ADC has a 7 to 8 SN-38 per antibody (i.e., DAR ≈8) (see page 920, left col.).
With respect to instant claim 15, Govindan teaches that the immunoconjugates can be formulated into a pharmaceutical composition comprising a buffer (see claims 59 and 60).
Govindan fails to teach of an immunoconjugate comprising an FL118 drug. However, Ling teaches of several camptothecin analogues such as irinotecan, topotecan, and SN-38 (see entire document). Additionally, Ling teaches of FL118 which has exceptional antitumor activity (see Introduction). Further, while mutation of Top1 in prostate cancer cells strikingly increases resistance to camptothecin, SN-38, and topotecan, FL118 is much less affected (see page 1766, left col.). Also, Ling teaches that SN-38 and topotecan are substrates of the drug efflux pump ABCG2; in contrast, FL118 is a poor substrate of ABCG2, and over-expression of ABCG2 in cancer cells induces no resistance to FL118 (see page 1766, left col.).
As such, it would have been obvious at the time of the present invention to modify the immunoconjugate of Govindan comprising SN-38, an acid-sensitive linker (i.e., CL2A), and an antibody (e.g., hRS7) with the FL118 drug of Ling because Govindan discloses that the hRS7-CL2A-SN-38 ADC demonstrated enhanced cytotoxicity in several tumor models (see Examples 11 and 14-17). However, as established by Ling, SN-38 and FL118 are both camptothecin analogues. Additionally, mutations of Top1 increases resistance to SN-38 and SN-38 is a substrate of the drug efflux pump ABCG2 whereas FL118 is not as affected by Top1 or over-expression. Further, because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable to one of ordinary skill in the art. Thus, one would have a reasonable expectation that substituting the SN-38 of Govindan with FL118 would enhance the cytotoxicity of the immunoconjugate.
Furthermore, Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
Generally, 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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, antibody-drug conjugates, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed antibody-drug conjugates are akin to the variables discussed in the cited MPEP passage, because said antibody-drug conjugates are optimizable variables that would affect at least the toxicity and/or efficacy, i.e., function, of the claimed invention. Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize the camptothecin drug of the conjugate, because such optimization would produce a more effective invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to antibody-drug conjugates which achieves a recognized result, such as drug toxicity and/or therapeutic benefit. Accordingly the recited antibody-drug conjugates are result-effective variables that achieve a recognized result, such as drug toxicity and/or therapeutic benefit for a patient with a tumor, and it is submitted that since one of ordinary skill in the art would have thus been motivated to determine the optimum camptothecin drug of said variable, the antibody-drug conjugates recited were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
Cardillo and Ling
Claims 1-23 are rejected under 35 U.S.C. 103 as being unpatentable over Cardillo et al1 (Bioconjugate Chem. 2015, 26, 919−931), as evidenced by Cardillo et al2 (Clin Cancer Res. 2011 May 15; 17(10): 3157–3169), and further in view of Ling et al (Am J Transl Res 2015;7(10):1765-1781; previously submitted with the Restriction Requirement filed on 11/19/2025).
With respect to the instant claims, Cardillo1 teaches of Sacituzumab govitecan (IMMU-132) which is an ADC comprising a humanized anti-Trop-2 monoclonal antibody (hRS7) conjugated with the active metabolite of irinotecan, SN-38 (see Abstract). Unlike most ADCs that use ultratoxic drugs and stable linkers, IMMU-132 uses a moderately toxic drug with a moderately stable carbonate bond between SN-38 and the linker (see Abstract). Cardillo1 disclose that the carbonate linker is used that is cleavable at low pH but will also release the drug with a half-life in serum of ~24 h (see page 925, left col.). Additionally, the SN-38 is conjugated to 8 interchain thiols of the antibody (see page 925, left col.). Cardillo1 disclose that IMMU-132 has 7 to 8 SN-38 per antibody (i.e., DAR ≈8) (see page 920, left col.). Cardillo1 disclose that IMMU-132 has demonstrated significant antitumor activity against a wide range of tumor types (see page 920, left col.). Cardillo1 teaches that IMMU-132 is composed of an antibody that internalizes after binding to an epitope (see page 925, left col.), and SN-38 readily penetrates cell membranes (see page 925, right col.). While Cardillo1 does not show the structure of IMMU-132, it is known that the linker of IMMU-132 is a species of instant Formula 2 as evidenced by Cardillo2 (see below).
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Cardillo1 fails to teach of an immunoconjugate comprising an FL118 drug. However, Ling teaches of several camptothecin analogues such as irinotecan, topotecan, and SN-38 (see entire document). Additionally, Ling teaches of FL118 which has exceptional antitumor activity (see Introduction). Further, while mutation of Top1 in prostate cancer cells strikingly increases resistance to camptothecin, SN-38, and topotecan, FL118 is much less affected (see page 1766, left col.). Also, Ling teaches that SN-38 and topotecan are substrates of the drug efflux pump ABCG2; in contrast, FL118 is a poor substrate of ABCG2, and over-expression of ABCG2 in cancer cells induces no resistance to FL118 (see page 1766, left col.).
As such, it would have been obvious at the time of the present invention to modify the immunoconjugate of Cardillo1 comprising SN-38, an acid-sensitive linker (i.e., CL2A), and an antibody (e.g., hRS7) with the FL118 drug of Ling because Cardillo1 discloses that the hRS7-CL2A-SN-38 ADC demonstrated enhanced cytotoxicity in several tumor models (see page 920, left col.). However, as established by Ling, SN-38 and FL118 are both camptothecin analogues. Additionally, mutations of Top1 increases resistance to SN-38 and SN-38 is a substrate of the drug efflux pump ABCG2 whereas FL118 is not as affected by Top1 or over-expression. Further, because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable to one of ordinary skill in the art. Thus, one would have a reasonable expectation that substituting the SN-38 of Cardillo1 with FL118 would enhance the cytotoxicity of the immunoconjugate.
Furthermore, Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
Generally, 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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, antibody-drug conjugates, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed antibody-drug conjugates are akin to the variables discussed in the cited MPEP passage, because said antibody-drug conjugates are optimizable variables that would affect at least the toxicity and/or efficacy, i.e., function, of the claimed invention. Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize the camptothecin drug of the conjugate, because such optimization would produce a more effective invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to antibody-drug conjugates which achieves a recognized result, such as drug toxicity and/or therapeutic benefit. Accordingly the recited antibody-drug conjugates are result-effective variables that achieve a recognized result, such as drug toxicity and/or therapeutic benefit for a patient with a tumor, and it is submitted that since one of ordinary skill in the art would have thus been motivated to determine the optimum camptothecin drug of said variable, the antibody-drug conjugates recited were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
Wong and Ling
Claims 1-23 are rejected under 35 U.S.C. 103 as being unpatentable over Wong et al (European Journal of Medicinal Chemistry 167 (2019) 583-593; previously submitted with the Restriction Requirement filed on 11/19/2025) and further in view of Ling et al (Am J Transl Res 2015;7(10):1765-1781; previously submitted with the Restriction Requirement filed on 11/19/2025).
With respect to the instant claims, Wong disclose of two ADCs of 7-ethyl-10-hydroxycamptothecin (SN-38): Sacituzumab govitecan and labetuzumab govitecan (see entire document). These two second-generation ADCs comprise higher DAR of 7-8, moderately-potent cytotoxic SN-38, and an intermediately stable linker (see page 584, right col.). Sacituzumab govitecan (IMMU-132) is favorably developed for treatment of diverse solid tumors such as colorectal cancer, pancreatic cancer, gastric cancer, triple negative breast cancer, (non) small cell lung cancer, and other epithelial tumors that highly express Trop-2 (see page 585, left col.). Wong disclose that SN-38 can exist partly as the active lactone form and partly as the inactive carboxylate form when it is exposed to physiological conditions (37°C, pH7.4) (see page 585). Wong disclose that the CL2A linker has three structural features, (i) maleimide chemistry to react with sulfhydryl groups of mAb, (ii) pH-sensitive carbonate, and (iii) a short PEG7 group to increase the water solubility of the linker and reduce P-glycoprotein-mediated drug resistance (see page 585, right col.); such a slight change does not affect CL1~CL5 to obtain the mean DAR of ~6 (see pages 585 and 586). Generally, the high DAR will be beneficial for ADCs’ efficacy in vivo (see page 586, left col.). When mAb-CL2A-SN-38 conjugates exist low pH, such as the tumor microenvironment or lysozyme in cancer cells, the carbonate is cleaved, and then the drug is released to produce anticancer effects (see page 586, left col.). The linker disclosed by Wong is a species of instant Formula 2 (see below).
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Wong fails to teach of an immunoconjugate comprising an FL118 drug. However, Ling teaches of several camptothecin analogues such as irinotecan, topotecan, and SN-38 (see entire document). Additionally, Ling teaches of FL118 which has exceptional antitumor activity (see Introduction). Further, while mutation of Top1 in prostate cancer cells strikingly increases resistance to camptothecin, SN-38, and topotecan, FL118 is much less affected (see page 1766, left col.). Also, Ling teaches that SN-38 and topotecan are substrates of the drug efflux pump ABCG2; in contrast, FL118 is a poor substrate of ABCG2, and over-expression of ABCG2 in cancer cells induces no resistance to FL118 (see page 1766, left col.).
As such, it would have been obvious at the time of the present invention to modify the immunoconjugate of Wong comprising SN-38, an acid-sensitive linker (i.e., CL2A), and an antibody (e.g., hRS7) with the FL118 drug of Ling because Wong discloses that the hRS7-CL2A-SN-38 ADC demonstrated enhanced cytotoxicity in several tumor models (see page 920, left col.). However, as established by Ling, SN-38 and FL118 are both camptothecin analogues. Additionally, mutations of Top1 increases resistance to SN-38 and SN-38 is a substrate of the drug efflux pump ABCG2 whereas FL118 is not as affected by Top1 or over-expression. Further, because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable to one of ordinary skill in the art. Thus, one would have a reasonable expectation that substituting the SN-38 of Wong with FL118 would enhance the cytotoxicity of the immunoconjugate.
Furthermore, Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
Generally, 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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, antibody-drug conjugates, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed antibody-drug conjugates are akin to the variables discussed in the cited MPEP passage, because said antibody-drug conjugates are optimizable variables that would affect at least the toxicity and/or efficacy, i.e., function, of the claimed invention. Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize the camptothecin drug of the conjugate, because such optimization would produce a more effective invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to antibody-drug conjugates which achieves a recognized result, such as drug toxicity and/or therapeutic benefit. Accordingly the recited antibody-drug conjugates are result-effective variables that achieve a recognized result, such as drug toxicity and/or therapeutic benefit for a patient with a tumor, and it is submitted that since one of ordinary skill in the art would have thus been motivated to determine the optimum camptothecin drug of said variable, the antibody-drug conjugates recited were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
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.
19/107,728
Claims 1-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-17, and 19 of copending Application No. 19/107,728 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With respect to the instant claims, the ‘728 application is drawn to an immunoconjugate or a pharmaceutically acceptable salt thereof, wherein a camptothecin-based drug (A) is bound, through a linker (C), to: an antibody or an antigen- binding site-containing fragment (B-1) thereof having a dissociation constant Kd value of 1*10-8 M or more to less than 1 * 10-6 M with respect to an epitope of a cell surface protein; or an antibody or antigen-binding site-containing fragment (B-2) thereof that binds to a cell surface protein expressed in both normal cells and cancer cells and has a higher binding affinity with respect to an epitope of the cell surface protein when binding divalently than when binding monovalently (see claim 1). The ‘728 application is drawn to the immunoconjugate or pharmaceutically acceptable salt thereof of claim 1, wherein the linker (C) is (i) an acid-sensitive linker or (ii) an enzyme-sensitive linker (see claim 9). The ‘728 application is drawn to the immunoconjugate or pharmaceutically acceptable salt thereof of claim 9, wherein after being targeted to cancer cells by an antigen-binding site that targets an antigen of cancer cells, an acid-sensitive linker is decomposed in the acidic environment (pH ≤ 7) around cancer cells such that at least a portion of the camptothecin-based drug is released, thereby releasing a drug both inside and outside cells (see claim 15).
With respect to instant claim 3, the ‘728 application is drawn to immunoconjugate or pharmaceutically acceptable salt thereof of claim 9, wherein when an acid-sensitive linker is decomposed, the camptothecin-based drug and the acid-sensitive linker are linked by a carbonate or ester bond, so as to release a free camptothecin-based drug (see claim 16).
With respect to instant claim 7, the ‘728 application is drawn to the immunoconjugate or pharmaceutically acceptable salt thereof of claim 1, wherein an antibody or an antigen-binding site-containing fragment thereof (B) that binds to a cell surface protein selected from the group consisting of Her2, EGFR, Trop2, c-Met, CEACAM-5, B7H3, B7H4, Mul, CDH6, CLDN18.2, FolR and PSMA is used (see claim 12).
With respect to instant claims 8-9 and 16-17, the ‘728 application is drawn to the immunoconjugate or pharmaceutically acceptable salt thereof of claim 9, wherein the acid-sensitive linker is derived from Chemical Formula 7 below:
[Chemical Formula 7]
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With respect to instant claim 14, the ’728 application is drawn to the immunoconjugate or pharmaceutically acceptable salt thereof of claim 1, wherein the immunoconjugate or pharmaceutically acceptable salt thereof has a DAR of 4 to 8 that indicates the number of drugs attached per antibody with respect to the antibody, or a DAR of 1 to 4 with respect to the antigen-binding site-containing fragment (see claim 8).
With respect to instant 15, the ‘728 application is drawn to a pharmaceutical composition for preventing or treating cancer, comprising the immunoconjugate or pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient (see claim 19).
As such, the ‘728 application anticipates the present invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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