Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 1-26 are pending in the instant application and being examined on the merit.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e)
or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not
complied with one or more conditions for receiving the benefit of an earlier filing date
under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention
which is also disclosed in the prior application (the parent or original nonprovisional
application or provisional application). The disclosure of the invention in the parent
application and in the later-filed application must be sufficient to comply with the
requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112,
except for the best mode requirement. See Transco Products, Inc. v. Performance
Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed priority application 63/236,988, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Claim analysis of previous priority applications reveal the effective filing dates of claims are drawn to two separate applications, namely, the earliest priority application 63/236,988 (8/25/2021) and 63/272,450 (10/27/2021). The earliest priority
application specifically lacks priority for a method of reducing toxicity associated with target-mediated cross-reactivity in a subject by administering an antibody-drug conjugate (ADC) of formula (I) to the subject, wherein W1 is an antibody binding to an antigen; and wherein the administering reduces the toxicity in the subject associated with target-mediated cross-reactivity of the ADC. Thus, claims 1-26 contain subject matter introduced for the first time in 63/272,450. Claims 1-26 are present in the
provisional application 63/272,450 and have the priority date of 10/27/2021.
Claim Interpretation
Regarding instant claim 9, the instant specification taught a vital organ of a subject is an organ that is essential for survival of a living subject; For example, the vital organ can be any of brain, heart, lung, liver, kidney or spleen. (page 8, [0036]). The skin is also considered a vital organ the prior art (NCI SEER Training Module. Anatomy of the Skin, (https://web.archive.org/web/20201014122814/https://training.seer.cancer. gov/melanoma/anatomy/ 2020), first paragraph).
Objections to the Drawings and Specification
The disclosure is objected to because of the following informalities: Figures 9A and 9C contain amino acid sequences of four or more amino acids, but does not include a SEQ ID NO in the drawings or the Brief Description of the Drawings in the specification. Regarding Fig. 9A, The specification indicates the heavy chain as “(GenBank Accession No. AAG00909; SEQ ID NO://)” on page 9 [0048]. Regarding Fig. 9C, The specification lists an alignment of immunoglobulin light chain constant regions “(from top to bottom SEQ ID NOs: 163, //, //,//,and 175)”, on page 9 [0050].
The peptide sequences are required to be identified in the Brief Description of the Drawings to obviate this rejection.
Amendment to the Brief Description of the Drawings with the SEQ ID Nos: 37 C.F.R. 1.831 Requirements for patent applications filed on or after July 1, 2022, having nucleotide and/or amino acid sequence disclosures. Where a sequence is presented in a drawing, reference must be made to the sequence by use of the sequence identifier (§ 1.832(a) ), either in the drawing or in the Brief Description of the Drawings, where the correlation between multiple sequences in the drawing and their sequence identifiers (§ 1.832(a) ) in the Brief Description is clear.
Appropriate correction is required.
Claim Rejections – 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 24-25 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Regarding instant claims 24-25, Formula (I) already contains the anticancer drug maytansine which is a maytansinoid. Thus, instant claims 24-25 fail to further limit the scope of the parent claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections – 35 USC § 112(a)
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 10, 21, and 26 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 specification does not show that the Applicant possessed an effective method of non-parenteral administration of an antibody-drug conjugate (ADC) of Formula (I). The specification only shows ADC administration was effective via intravenous administration.
The Applicant was not in possession of a method of reducing toxicity associated with target-mediated cross-reactivity in a subject by administering the ADC of formula (I), wherein toxicity is reduced by two-fold or otherwise compared to when the subject is administered an ADC targeting the same antigen and comprising a linker and a payload different from the ADC of formula (I) as claimed. No structure activity relationship was shown in the disclosure that would allow any antibody, targeting an antigen, with any linker, with any payload, with any dose to reduce toxicity as claimed.
Scope of the claimed genus
Instant claim 21 claims a method of reducing toxicity associated with target-mediated cross-reactivity in a subject by administering an antibody-drug conjugate (ADC) of formula (I) to the subject, wherein W1 is an antibody binding to an antigen; and wherein the administering reduces the toxicity in the subject associated with target-mediated cross-reactivity of the ADC, wherein the ADC of formula (I) is administered non-parenterally;
Instant claims 10 and 26, claim a method of reducing toxicity associated with target-mediated cross-reactivity in a subject by administering the ADC of formula (I), wherein toxicity is reduced by two-fold or otherwise compared to when the subject is administered an ADC targeting the same antigen and comprising a linker and a payload different from the ADC of formula (I) as claimed.
Summary of Species disclosed in the original specification
The instant specification has 0 examples of antibody-drug conjugates effectively administered non-parenterally. Intravenous injection was used in rats and mice (page 83, [00332-00333];
The instant specification shows an anti-nectin-4 antibody conjugated to vedotin was more toxic in comparison to an Anti-nectin-4 conjugated RED-106 (Fig. 2). Thus, one different linker with one different drug was tested.
State of the Relevant Art
The prior art has taught parenteral administration of antibody-drug conjugates. Li F et al. (Mol Cancer Ther (2019) 18 (4) 780–787.) taught intravenous and intraperitoneal injection of antibody-drug conjugates and that these routes of administration were effective in subjects (Fig. 2-3). The prior art after the filing date of the instant application has shown that while there are several routes of administration for unconjugated antibodies, there are limitations to each of the methods (Pitiot A et al. (Antibodies 2022, 11, 56 1-25). Pitiot taught apart from the most commonly used IV route, topical delivery of Abs has shown clinical successes, however, additional research is necessary to understand the consequences of biological barriers associated with local delivery for Ab partitioning, in order to optimize delivery methods and devices, and to adapt Ab formulation to local delivery (abstract). Pitiot taught non-parenteral antibody administration via inhalation has multiple biological barriers and a high potential for aggregation
PNG
media_image1.png
537
964
media_image1.png
Greyscale
(Pitiot Table 9). The prior art administers antibody-drug conjugates parenterally.
No structure activity relationship has been identified in the prior art that would allow any antibody, targeting an antigen, with any linker, with any payload, with any dose to reduce toxicity as claimed. The breadth of the ADC claimed is very large. Regarding linkers, the prior art has shown that thioether linkage in an ADC undergoes deconjugation through a retro-Michael pathway, leading to loss of cargo and reduction in efficacy, wherein the maleimide-cargo conjugate can then be bound to other plasma thiols including human serum albumin leading to off-site toxicity and reduced efficacy (Szijj PA et al. (Drug Discovery Today: Technologies 2018 30 27-34) page 28, left to right column bridging paragraph and Scheme 1a). Further, Staudacher AH et al. (Br J Cancer 2017 117(12):1736-1742.) taught ADCs with non-cleavable linkers have particular advantages: high stability in serum, manifest anti-tumor activity only after internalization and lysosomal degradation, and greatest anti-tumor efficacy with high and homogenous tumor expression of target antigen (page 1738, left column, second to last paragraph). Staudacher taught these ADCs do not cause bystander killing because only the tumor cells that have internalized the ADC are killed with little or no effect on surrounding, antigen-negative cells (page 1738, left column, second to last paragraph). Thus, while several non-cleavable linkers would be known to be less toxic than cleavable linkers, the Applicant has not tested the array of necessary antibodies, linkers, and payloads with any dose to reduce toxicity as claimed. Additionally, WO 2019/118411 (Maclaren A et al.) taught a method of administration of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 6 or 20 mg/kg CAT-02-106 to a subject did not result in a bodyweight change of >10%, while 60 mg/kg resulted in a bodyweight reduction of >10% (page 21, [0074] and Fig. 20), wherein the dose was administered parenterally (page 144, [00503]). Thus, dosage can also affect toxicity of the instantly claimed formula (I) wherein all else is equal.
Claim 21 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an effective method of parenteral administration of an antibody-drug conjugate (ADC) of Formula (I), does not reasonably provide enablement for effective method of non-parenteral administration of an antibody-drug conjugate (ADC) of Formula (I).The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
The specification and prior art does not show that the Applicant is enabled for an effective method of non-parenteral administration of an antibody-drug conjugate (ADC) of Formula (I). The specification and prior art only show ADC administration was effective via parenteral administration.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These
factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Scope of the claimed genus and nature of the invention.
Instant claim 21 claims a method of reducing toxicity associated with target-mediated cross-reactivity in a subject by administering an antibody-drug conjugate (ADC) of formula (I) to the subject, wherein W1 is an antibody binding to an antigen; and wherein the administering reduces the toxicity in the subject associated with target-mediated cross-reactivity of the ADC, wherein the ADC of formula (I) is administered non-parenterally.
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
The instant specification has 0 examples of antibody-drug conjugates effectively administered non-parenterally. Intravenous injection was used in rats and mice (page 83, [00332-00333]. The instant specification only states in some aspects, the antibody-drug conjugate (ADC) of formula (I) is administered to the subject non-parenterally (page 8, [0032]) and that oral or topical administration can be formulated (page 80, [00322].
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art.
The prior art has taught parenteral administration of antibody-drug conjugates.
Li F et al. (Mol Cancer Ther (2019) 18 (4) 780–787.)
taught intravenous and intraperitoneal injection of antibody-drug conjugates and that these routes of administration were effective in subjects (Fig. 2-3). The prior art after the filing date of the instant application has shown that while there are several routes of administration for unconjugated antibodies, there are limitations to each of the methods (Pitiot A et al. (Antibodies 2022, 11, 56 1-25). Pitiot taught apart from the most commonly used IV route, topical delivery of Abs has shown clinical successes, however, additional research is necessary to understand the consequences of biological barriers associated with local delivery for Ab partitioning, in order to optimize delivery methods and devices, and to adapt Ab formulation to local delivery (abstract). Pitiot taught non-parenteral antibody administration via inhalation has multiple biological barriers and a high potential for aggregation
PNG
media_image1.png
537
964
media_image1.png
Greyscale
(Pitiot Table 9). The prior art administers antibody-drug conjugates parenterally.
Claim Rejections – 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 6, 10-11, 14-15, 19-20, 22-26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2019/118411 (Maclaren A et al.) and evidenced by NCI drug Dictionary TRPH-222 (https://www.cancer.gov/publications/dictionaries/ cancer-drug/def/anti-cd22-adc-trph-222, 2026) and Kato J et al. (Oncoimmunology. 2012 Dec 1;1(9):1469–1475).
The instant specification taught the methods of the present invention include a method of reducing the target-mediated cross-reactivity of an ADC in a subject, wherein this phenomenon is understood to be target-mediated cross-reactivity and as an implication of this, particularly, as a result of delivery of the drug of the ADC to healthy cells, the subject might show any or a combination of clinical indications or reactions that include but are not limited to instant Table 2 (specification, pages 32-33, [00172] and Table 2). Instant Table 2 indicates bodyweight changes as a parameter
PNG
media_image2.png
46
645
media_image2.png
Greyscale
PNG
media_image3.png
74
676
media_image3.png
Greyscale
Thus, treatment with an ADC with a bodyweight loss of <10% is a method of reducing the target-mediated cross-reactivity of an ADC in a subject. Maclaren taught a method of administration of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 6 or 20 mg/kg CAT-02-106 to a subject did not result in a bodyweight change of >10%, while 60 mg/kg resulted in a bodyweight reduction of >10% (page 21, [0074] and Fig. 20), wherein the dose was administered parenterally (page 144, [00503]).
Regarding instant claims 1, 6, 10-11, 14-15, 19-20, 22-25, Maclaren taught an effective method of treating cancer, which is a proliferative disorder (instant claim 11), that expressed CD22 comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 10 mg/kg CAT-02-106 (page 20, [0071] and Fig. 17) which targeted CD22, wherein subject body weight was not affected by treatment with the ADC (Fig. 19). Thus, treatment with an ADC with a bodyweight loss of <10% is a method of reducing the target-mediated cross-reactivity of an ADC in a subject. Regarding the structure of CAT-02-106: i) the NCI drug Dictionary taught TRPH-222 is also known as CAT-02-106 and is a monoclonal antibody (instant claim 22) (NCI TRPH-222 page 1); and ii) Maclaren taught conjugation of a humanized (instant claim 23) anti-CD22 antibody CAT-02 to a linker maytansine payload (instant claim 24-25) via a C-terminally tagged formylglycine aldehyde tagged antibody (page 157, [00556]) wherein the linker maytansine is RED-106 (page 154, scheme and pages 156-157, [00553]), wherein the aldehyde tag is LCTPSR (SEQ ID NO: 32) with the C converted to formylglycine (instant claim 14) with formylglycine generating enzyme (FGE) (pages 142-143, [00496]) to yield Leu-fGly-Thr-Pro-Ser-Arg (instant claim 6), wherein the aldehyde tag sequence was inserted at the heavy chain C-terminus which is the CH3 (instant claim 15 and 19) (pages 142-143, [00496]), and wherein the antibody conjugated ADC had the structure
PNG
media_image4.png
259
495
media_image4.png
Greyscale
bound to fGly’ (page 118, [00432]), which would naturally have a reduced toxicity compared to when the subject is administered an ADC targeting the same antigen and comprising a linker and a payload different from the ADC of formula (I) (instant claim 10) (instant claim 1). Maclaren taught subjects are dosed parenterally with CAT-02-106 (page 162, [00565])(instant claim 20). The above method naturally reduces toxicity associated with target-mediated cross-reactivity of the administered ADC in a subject.
Regarding instant claim 26, the method of Maclaren above comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 10 mg/kg CAT-02-106 (page 20, [0071] and Fig. 17) which targeted CD22, wherein subject body weight was not affected by treatment with the ADC (Fig. 19) has a toxicity reduced in the subject by at least 2 folds when the ADC of Formula (I) is administered, as compared to administering the subject an antibody-drug conjugate targeting the same antigen and comprising a linker and a payload different from the ADC of formula (I) as evidenced by Kato. Kato taught administration of a pharmaceutical composition comprising a pharmaceutical excipient and 1 mg/kg HB22.7-SAP, which targets CD22 (Kato abstract), results in a loss of more than 10% bodyweight (Kato Fig. 3B), which is a reduced toxicity of more than 2-fold compared to CAT-02-106.
Claim Rejections – 35 USC § 103
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 for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 6, 10-13, 14-20, 22-26 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/118411 (Maclaren A et al.), WO 2015/187428 (Rabuka D et al.), and Staudacher AH et al. (Br J Cancer 2017 117(12):1736-1742.) and evidenced by NCI drug Dictionary TRPH-222 (https://www.cancer.gov/publications/dictionaries/ cancer-drug/def/anti-cd22-adc-trph-222, 2026) and Kato J et al. (Oncoimmunology. 2012 Dec 1;1(9):1469–1475).
Maclaren taught the limitations of claims 1, 6, 10-11, 14-15, 19-20, 22-26 for the reasons set forth above.
Maclaren is described above. Maclaren further taught: an aldehyde tag can be present: i) at or near the C-terminus of an Ig heavy chain; ii) within a CH1 domain of an Ig heavy chain; iii) within a CH2 domain of an Ig heavy chain; iv) within a CH3 domain of an Ig heavy chain; v) in an Ig kappa or lambda light chain constant region (page 82, [00339]). Maclaren taught an aldehyde tag in IgG1 (page 89, [00356] and Fig. 9)
Maclaren did not teach a single embodiment of the method wherein the ADC: 1) is positioned in a light chain constant region; 2) is positioned in a heavy chain CH1 constant region; 3) is positioned in a heavy chain CH2 constant region; 4) is an IgG1 kappa antibody, but this is obvious in view of Rabuka and Staudacher.
Rabuka taught the aldehyde tags in trastuzumab and cloned into the constant regions of a prototype human IgG1 heavy chain and kappa light chain wherein the aldehyde tag was well-tolerated when inserted into a variety of locations along the antibody backbone and the tagged antibodies showed no to very little aggregation in: a light chain constant region after A153 (LC); heavy chain CH1 region after G118; and heavy chain CH2 region after N344 in the antibody (pages 144-145, [00436-00438] and Table 2).Rabuka taught the unconjugated and ADC versions of LC-, CH1-, and CT-tagged antibodies were poorly immunogenic (pages 147-148, [00443] and Table 5). Rabuka taught administration of a pharmaceutical composition comprising anti-HER2 ADCs conjugated via aldehyde tags at different locations within the antibody such as CH1, LC, and the C terminal were effective at treating HER2 positive cancer (Fig. 11A).
Staudacher taught ADCs with non-cleavable linkers have particular advantages: high stability in serum, manifest anti-tumor activity only after internalization and lysosomal degradation, and greatest anti-tumor efficacy with high and homogenous tumor expression of target antigen (page 1738, left column, second to last paragraph). Staudacher taught these ADCs do not cause bystander killing because only the tumor cells that have internalized the ADC are killed with little or no effect on surrounding, antigen-negative cells (page 1738, left column, second to last paragraph).
Regarding instant claims 12-13 and 16-18, it would have been obvious for a person having ordinary skill in the art to modify the method of Maclaren above of treating cancer that expressed CD22 comprising parenterally administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 10 mg/kg CAT-02-106 which targeted CD22, wherein subject body weight was not affected by treatment with the ADC, wherein CAT-02-106 is an anti-CD22 humanized monoclonal antibody CAT-02 with a C-terminal tagged formylglycine aldehyde tag of Leu-fGly-Thr-Pro-Ser-Arg conjugated to RED-106, wherein the aldehyde tag sequence was inserted at the heavy chain C-terminus which is the CH3, and wherein the antibody conjugated ADC had the structure bound to fGly’
PNG
media_image4.png
259
495
media_image4.png
Greyscale
- by:
1) exchanging the anti-CD22 antibody for a CD22 expressing cancer to an anti-HER2 IgG1 kappa antibody trastuzumab for a HER2 high expressing cancer wherein the aldehyde tag is positioned in: i) a light chain constant region; ii) a heavy chain CH1 constant region; iii) a heavy chain CH2 constant region in view of Maclaren and Rabuka.
This is obvious because Maclaren taught: an aldehyde tag can be present: i) at or near the C-terminus of an Ig heavy chain; ii) within a CH1 domain of an Ig heavy chain; iii) within a CH2 domain of an Ig heavy chain; iv) within a CH3 domain of an Ig heavy chain; v) in an Ig kappa or lambda light chain constant region; and in IgG1; and:
1a) Rabuka taught the aldehyde tags in trastuzumab and cloned into the constant regions of a prototype human IgG1 heavy chain and kappa light chain wherein the aldehyde tag was well-tolerated when inserted into a variety of locations along the antibody backbone and the tagged antibodies showed no to very little aggregation in: a light chain constant region after A153 (LC); heavy chain CH1 region after G118; and heavy chain CH2 region after N344 in the antibody; and
1b) Rabuka taught the unconjugated and ADC versions of LC-, CH1-, and CT-tagged antibodies were poorly immunogenic and administration of a pharmaceutical composition comprising anti-HER2 ADCs conjugated via aldehyde tags at different locations within the antibody such as CH1, LC, and the C terminal were effective at treating HER2 positive cancer.
There is a reasonable expectation of success because:
1a) Rabuka taught the aldehyde tags in trastuzumab and cloned into the constant regions of a prototype human IgG1 heavy chain and kappa light chain wherein the aldehyde tag was well-tolerated when inserted into a variety of locations along the antibody backbone and the tagged antibodies showed no to very little aggregation in: a light chain constant region after A153 (LC); heavy chain CH1 region after G118; and heavy chain CH2 region after N344 in the antibody; and
1b) Rabuka taught the unconjugated and ADC versions of LC-, CH1-, and CT-tagged antibodies were poorly immunogenic and administration of a pharmaceutical composition comprising anti-HER2 ADCs conjugated via aldehyde tags at different locations within the antibody such as CH1, LC, and the C terminal were effective at treating HER2 positive cancer.
Thus, a trastuzumab aldehyde tag conjugated ADC at these positions would be expected to be effective.
1c) Staudacher taught: i) ADCs with non-cleavable linkers have particular advantages: high stability in serum, manifest anti-tumor activity only after internalization and lysosomal degradation, and greatest anti-tumor efficacy with high and homogenous tumor expression of target antigen; and ii) these ADCs do not cause bystander killing because only the tumor cells that have internalized the ADC are killed with little or no effect on surrounding, antigen-negative cells. Thus, exchange to the anti-HER2 antibody with the non-cleavable linker of RED-106 would not be expected to be as toxic to surrounding tissues that express less HER2.
This would produce a method of Maclaren and Rabuka of treating cancer that expressed HER2 comprising parenterally administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and Trastuzumab-106 which targeted HER2, wherein subject body weight was not affected by treatment with the ADC, wherein trastuzumab-106 is an anti-HER2 humanized monoclonal IgG1 kappa antibody (instant claims 12-13) with a formylglycine aldehyde tag of Leu-fGly-Thr-Pro-Ser-Arg conjugated to RED-106, wherein the aldehyde tag sequence was positioned in: i) the heavy chain C-terminus which is the CH3; ii) a light chain constant region; iii) a heavy chain CH1 constant region; iv) a heavy chain CH2 constant region (instant claims 16-18), wherein the antibody conjugated ADC had the structure bound to fGly’
PNG
media_image4.png
259
495
media_image4.png
Greyscale
, and wherein the method naturally reduces toxicity associated with target-mediated cross-reactivity of the administered ADC in a subject.
Claims 1, 2-4, 6, 9-11, 14-15, 19-20, 22-26 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/118411 (Maclaren A et al.) and Challita-Eid PM et al. (Cancer Res 2016 76(10) 3003–3013.) and Staudacher AH et al. (Br J Cancer 2017 117(12):1736-1742.) and evidenced by NCI drug Dictionary TRPH-222 (https://www.cancer.gov/publications/dictionaries/ cancer-drug/def/anti-cd22-adc-trph-222, 2026) and Kato J et al. (Oncoimmunology. 2012 Dec 1;1(9):1469–1475).
Maclaren taught the limitations of claims 1, 6, 10-11, 14-15, 19-20, 22-26 for the reasons set forth above.
Maclaren is described above.
Maclaren did not teach an ADC comprising an anti-nectin-4 antibody and that nectin-4 is expressed on skin, but this is obvious in view of Challita-Eid and Staudacher.
Challita-Eid taught an effective method of treatment of mouse xenograft models of human breast, bladder, pancreatic, and lung cancers comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and enfortumab vedotin significantly inhibited the growth of all four tumor types and resulted in tumor regression of breast and bladder xenografts (abstract and Fig. 6). Challita-Eid taught nectin-4 as an attractive therapeutic target in multiple solid tumors and support further clinical development, investigation, and application of nectin-4–targeting ADCs (abstract). Challita-Eid taught Nectin-4 expression was detected in the epithelia of bladder, breast, stomach, esophagus, salivary gland (ducts), and skin (epidermis and sweat glands)(page 3010, right column, first paragraph), but with weak to moderate staining in human skin keratinocytes, skin appendages (sweat glands and hair follicles), transitional epithelium of bladder, salivary gland (ducts), esophagus, breast, and stomach (page 3005, right column, Results, first paragraph). Challita-Eid taught 60% of bladder and 53% of breast cancer specimens showed either strong or moderate staining, with approximately equal percentages within each tumor type. (page 3012, left column, first paragraph and Fig. 2).
Staudacher taught ADCs with non-cleavable linkers have particular advantages: high stability in serum, manifest anti-tumor activity only after internalization and lysosomal degradation, and greatest anti-tumor efficacy with high and homogenous tumor expression of target antigen (page 1738, left column, second to last paragraph). Staudacher taught these ADCs do not cause bystander killing because only the tumor cells that have internalized the ADC are killed with little or no effect on surrounding, antigen-negative cells (page 1738, left column, second to last paragraph).
Regarding instant claims 2-4 and 9, it would have been obvious for a person having ordinary skill in the art to modify the method of Maclaren above of treating cancer that expressed CD22 comprising parenterally administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 10 mg/kg CAT-02-106 which targeted CD22, wherein subject body weight was not affected by treatment with the ADC, wherein CAT-02-106 is an anti-CD22 humanized monoclonal antibody CAT-02 with a C-terminal tagged formylglycine aldehyde tag of Leu-fGly-Thr-Pro-Ser-Arg conjugated to RED-106, wherein the aldehyde tag sequence was inserted at the heavy chain C-terminus which is the CH3, and wherein the antibody conjugated ADC had the structure
PNG
media_image4.png
259
495
media_image4.png
Greyscale
- by:
1) exchanging the anti-CD22 antibody for a CD22 expressing cancer to an anti-nectin-2 antibody enfortumab for a nectin-2 high expressing cancer in view of Challita-Eid.
This is obvious because:
1a) Challita-Eid taught an effective method of treatment of mouse xenograft models of human breast, bladder, pancreatic, and lung cancers comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and enfortumab vedotin significantly inhibited the growth of all four tumor types and resulted in tumor regression of breast and bladder xenografts;
1b) Challita-Eid taught nectin-4 as an attractive therapeutic target in multiple solid tumors and support further clinical development, investigation, and application of nectin-4–targeting ADCs;
1c) Challita-Eid taught Nectin-4 expression was detected in the epithelia of bladder, stomach, esophagus, salivary gland, and skin, but with weak or moderate staining; while bladder and breast cancer specimens showed stronger staining, with approximately equal percentages within each tumor type.
There is a reasonable expectation of success because:
1a) Challita-Eid taught an effective method of treatment of mouse xenograft models of human breast, bladder, pancreatic, and lung cancers comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and enfortumab vedotin significantly inhibited the growth of all four tumor types and resulted in tumor regression of breast and bladder xenografts;
1b) Challita-Eid taught nectin-4 as an attractive therapeutic target in multiple solid tumors and support further clinical development, investigation, and application of nectin-4–targeting ADCs;
1c) Challita-Eid taught Nectin-4 expression was detected in the epithelia of bladder, stomach, esophagus, salivary gland, and skin, but with weak or moderate staining; while bladder and breast cancer specimens showed stronger staining, with approximately equal percentages within each tumor type.
1d) Staudacher taught: i) ADCs with non-cleavable linkers have particular advantages: high stability in serum, manifest anti-tumor activity only after internalization and lysosomal degradation, and greatest anti-tumor efficacy with high and homogenous tumor expression of target antigen; and ii) these ADCs do not cause bystander killing because only the tumor cells that have internalized the ADC are killed with little or no effect on surrounding, antigen-negative cells. Thus, exchange to enfortumab with the non-cleavable linker of RED-106 would not be expected to be toxic to the skin, which also expresses nectin-4 but at lower levels.
This would produce a method of Maclaren, Challita-Eid, and Staudacher of treating cancer that expressed nectin-4 comprising parenterally administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 10 mg/kg enfortumab-106 which targeted nectin-4 (instant claims 3-4), which is expressed in skin (instant claim 2) which is a vital organ (instant claim 9), wherein subject body weight or skin was naturally not affected by treatment with the ADC, wherein enfortumab-106 is an anti-nectin antibody with a formylglycine aldehyde tag of Leu-fGly-Thr-Pro-Ser-Arg conjugated to RED-106, wherein the aldehyde tag sequence was positioned in the heavy chain C-terminus, wherein the antibody conjugated ADC had the structure bound to fGly’
PNG
media_image4.png
259
495
media_image4.png
Greyscale
, wherein the method naturally reduces toxicity associated with target-mediated cross-reactivity of the administered ADC in a subject.
Claims 1, 6, 8, 10-11, 14-15, 19-20, 22-26 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/118411 (Maclaren A et al.) and Hofland P et al. (ADC Review, News, October 2017, https://www.adcreview.com/news/preclinical-data-supports-development-xmt-1536-broad-population-patients-ovarian-cancer/) and Staudacher AH et al. (Br J Cancer 2017 117(12):1736-1742.) and evidenced by NCI drug Dictionary TRPH-222 (https://www.cancer.gov/publications/dictionaries/ cancer-drug/def/anti-cd22-adc-trph-222, 2026) and Kato J et al. (Oncoimmunology. 2012 Dec 1;1(9):1469–1475).
Maclaren taught the limitations of claims 1, 6, 10-11, 14-15, 19-20, 22-26 for the reasons set forth above.
Maclaren is described above.
Maclaren did not teach an ADC comprising an anti- NaPi2b antibody, but this is obvious in view of Hofland and Staudacher.
Hofland taught the PBRM antibody XMT-1535 targeted the sodium-dependent phosphate transport protein (NaPi2b; SLC34A2) and that an XMT-1535 PBRM-linker-D
conjugate named XMT-1536 was highly potent (page 2, first paragraph). Hofland taught
NaPi2b is an antigen highly expressed in the majority of non-squamous NSCLC and epithelial ovarian cancer (page 2, first paragraph). Hofland taught the data support
NaPi2b as an outstanding target for ADC development (page 2, Outstanding target, first
paragraph)
Staudacher taught ADCs with non-cleavable linkers have particular advantages: high stability in serum, manifest anti-tumor activity only after internalization and lysosomal degradation, and greatest anti-tumor efficacy with high and homogenous tumor expression of target antigen (page 1738, left column, second to last paragraph). Staudacher taught these ADCs do not cause bystander killing because only the tumor cells that have internalized the ADC are killed with little or no effect on surrounding, antigen-negative cells (page 1738, left column, second to last paragraph).
Regarding instant claim 8, it would have been obvious for a person having ordinary skill in the art to modify the method of Maclaren above of treating cancer that expressed CD22 comprising parenterally administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 10 mg/kg CAT-02-106 which targeted CD22, wherein subject body weight was not affected by treatment with the ADC, wherein CAT-02-106 is an anti-CD22 humanized monoclonal antibody CAT-02 with a C-terminal tagged formylglycine aldehyde tag of Leu-fGly-Thr-Pro-Ser-Arg conjugated to RED-106, wherein the aldehyde tag sequence was inserted at the heavy chain C-terminus which is the CH3, and wherein the antibody conjugated ADC had the structure
PNG
media_image4.png
259
495
media_image4.png
Greyscale
- by:
1) exchanging the anti-CD22 antibody for a CD22 expressing cancer to an anti-NaPi2b antibody XMT-1535 for a NaPi2b high expressing cancer in view of Hofland.
This is obvious because:
1a) Hofland taught the PBRM antibody XMT-1535 targeted the sodium-dependent phosphate transport protein (NaPi2b; SLC34A2) and that an XMT-1535 PBRM-linker-D conjugate named XMT-1536 was highly potent;
1b) Hofland taught NaPi2b is an antigen highly expressed in the majority of non-squamous NSCLC and epithelial ovarian cancer;
1c) Hofland taught the data support NaPi2b as an outstanding target for ADC development;
There is a reasonable expectation of success because:
1a) Hofland taught the PBRM antibody XMT-1535 targeted the sodium-dependent phosphate transport protein (NaPi2b; SLC34A2) and that an XMT-1535 PBRM-linker-D conjugate named XMT-1536 was highly potent;
1b) Hofland taught NaPi2b is an antigen highly expressed in the majority of non-squamous NSCLC and epithelial ovarian cancer;
1c) Hofland taught the data support NaPi2b as an outstanding target for ADC development;
1d) Staudacher taught: i) ADCs with non-cleavable linkers have particular advantages: high stability in serum, manifest anti-tumor activity only after internalization and lysosomal degradation, and greatest anti-tumor efficacy with high and homogenous tumor expression of target antigen; and ii) these ADCs do not cause bystander killing because only the tumor cells that have internalized the ADC are killed with little or no effect on surrounding, antigen-negative cells. Thus, exchange to XMT-1536 with the non-cleavable linker of RED-106 would not be expected to be as toxic to surrounding tissues that express less NaPi2b.
This would produce a method of Maclaren, Hofland, and Staudacher of treating cancer with high expression of NaPi2b comprising parenterally administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 10 mg/kg XMT-1536-106 which targeted NaPi2b (instant claim 8) , wherein subject body weight was naturally not affected by treatment with the ADC, wherein XMT-1536-106 is an anti-NaPi2b antibody with a formylglycine aldehyde tag of Leu-fGly-Thr-Pro-Ser-Arg conjugated to RED-106, wherein the aldehyde tag sequence was positioned in the heavy chain C-terminus, wherein the antibody conjugated ADC had the structure bound to fGly’
PNG
media_image4.png
259
495
media_image4.png
Greyscale
, and wherein the method naturally reduces toxicity associated with target-mediated cross-reactivity of the administered ADC in a subject.
Claims 1, 6-7, 10-11, 14-15, 19-20, 22-26 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/118411 (Maclaren A et al.) and Bose M et al. (Vaccines (Basel) 2020 8(4):659) and Staudacher AH et al. (Br J Cancer 2017 117(12):1736-1742.) and evidenced by NCI drug Dictionary TRPH-222 (https://www.cancer.gov/publications/dictionaries/ cancer-drug/def/anti-cd22-adc-trph-222, 2026) and Kato J et al. (Oncoimmunology. 2012 Dec 1;1(9):1469–1475).
Maclaren taught the limitations of claims 1, 6, 10-11, 14-15, 19-20, 22-26 for the reasons set forth above.
Maclaren is described above.
Maclaren did not teach an ADC comprising an anti-Muc-1 antibody, but this is obvious in view of Bose and Staudacher.
Bose taught MUC1 is overexpressed and aberrantly glycosylated in most human epithelial cancers and is a highly overexpressed cell surface antigen and has altered glycosylation in tumors (page 3, Section 2.2, first paragraph). Bose taught humanized DS6 (huDS6) antibody conjugated to the cytotoxic maytansinoid derivative drug DM4 through a cleavable linker, SAR566658, showed antitumor efficacy against CA6-positive human pancreas, cervix, bladder, and ovary in vivo tumor xenograft models, with a minimal effective dose correlating with CA6 expression as well as better efficacy than standard-of-care nontargeted tubulin binders (page 9, second paragraph). Bose taught SAR566658 was used in a phase I clinical trial with 114 patients with refractory solid tumors and had a satisfactory safety profile and antitumor activity and was effective (page 9, second paragraph).
Staudacher taught ADCs with non-cleavable linkers have particular advantages: high stability in serum, manifest anti-tumor activity only after internalization and lysosomal degradation, and greatest anti-tumor efficacy with high and homogenous tumor expression of target antigen (page 1738, left column, second to last paragraph). Staudacher taught these ADCs do not cause bystander killing because only the tumor cells that have internalized the ADC are killed with little or no effect on surrounding, antigen-negative cells (page 1738, left column, second to last paragraph).
Regarding instant claim 7, it would have been obvious for a person having ordinary skill in the art to modify the method of Maclaren above of treating cancer that expressed CD22 comprising parenterally administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 10 mg/kg CAT-02-106 which targeted CD22, wherein subject body weight was not affected by treatment with the ADC, wherein CAT-02-106 is an anti-CD22 humanized monoclonal antibody CAT-02 with a C-terminal tagged formylglycine aldehyde tag of Leu-fGly-Thr-Pro-Ser-Arg conjugated to RED-106, wherein the aldehyde tag sequence was inserted at the heavy chain C-terminus which is the CH3, and wherein the antibody conjugated ADC had the structure bound to fGly’
PNG
media_image4.png
259
495
media_image4.png
Greyscale
- by:
1) exchanging the anti-CD22 antibody for a CD22 expressing cancer to an anti-Muc-1 antibody huDS6 for a Muc-1 high expressing cancer in view of Bose.
This is obvious because:
1a) Bose taught MUC1 is overexpressed and aberrantly glycosylated in most human epithelial cancers and is a highly overexpressed cell surface antigen and has altered glycosylation in tumors;
1b) Bose taught: i) humanized DS6 (huDS6) antibody conjugated to the cytotoxic maytansinoid derivative drug DM4 through a cleavable linker, SAR566658, showed antitumor efficacy against CA6-positive human pancreas, cervix, bladder, and ovary in vivo tumor xenograft models, with a minimal effective dose correlating with CA6 expression as well as better efficacy than standard-of-care nontargeted tubulin binders; and ii) SAR566658 was used in a phase I clinical trial with 114 patients with refractory solid tumors and had a satisfactory safety profile and antitumor activity and was effective.
There is a reasonable expectation of success because:
1a) Bose taught MUC1 is overexpressed and aberrantly glycosylated in most human epithelial cancers and is a highly overexpressed cell surface antigen and has altered glycosylation in tumors;
1b) Bose taught: i) humanized DS6 (huDS6) antibody conjugated to the cytotoxic maytansinoid derivative drug DM4 through a cleavable linker, SAR566658, showed antitumor efficacy against CA6-positive human pancreas, cervix, bladder, and ovary in vivo tumor xenograft models, with a minimal effective dose correlating with CA6 expression as well as better efficacy than standard-of-care nontargeted tubulin binders; and ii) SAR566658 was used in a phase I clinical trial with 114 patients with refractory solid tumors and had a satisfactory safety profile and antitumor activity and was effective.
1c) Staudacher taught: i) ADCs with non-cleavable linkers have particular advantages: high stability in serum, manifest anti-tumor activity only after internalization and lysosomal degradation, and greatest anti-tumor efficacy with high and homogenous tumor expression of target antigen; and ii) these ADCs do not cause bystander killing because only the tumor cells that have internalized the ADC are killed with little or no effect on surrounding, antigen-negative cells. Thus, exchange to huDS6 with the non-cleavable linker of RED-106 would not be expected to be as toxic to surrounding tissues that express less Muc-1.
This would produce a method of Maclaren, Bose, and Staudacher of treating cancer with high expression of NaPi2b comprising parenterally administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 10 mg/kg huDS6-106 which targeted Muc-1 (instant claim 7), wherein subject body weight was naturally not affected by treatment with the ADC, wherein huDS6-106 is an anti-Muc-1 antibody with a formylglycine aldehyde tag of Leu-fGly-Thr-Pro-Ser-Arg conjugated to RED-106, wherein the aldehyde tag sequence was positioned in the heavy chain C-terminus, wherein the antibody conjugated ADC had the structure bound to fGly’
PNG
media_image4.png
259
495
media_image4.png
Greyscale
, and wherein the method naturally reduces toxicity associated with target-mediated cross-reactivity of the administered ADC in a subject.
Claims 1, 5-6, 10-11, 14-15, 19-20, 22-26 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/118411 (Maclaren A et al.) and Okajima D et al. (Mol Cancer Ther (2019) 18 (12_Supplement): C026.) and Staudacher AH et al. (Br J Cancer 2017 117(12):1736-1742.) and evidenced by NCI drug Dictionary TRPH-222 (https://www.cancer.gov/publications/dictionaries/ cancer-drug/def/anti-cd22-adc-trph-222, 2026) and Kato J et al. (Oncoimmunology. 2012 Dec 1;1(9):1469–1475).
Maclaren taught the limitations of claims 1, 6, 10-11, 14-15, 19-20, 22-26 for the reasons set forth above.
Maclaren is described above.
Maclaren did not teach an ADC comprising an anti-TACSTD2, also known as Trop2, antibody, but this is obvious in view of Okajima and Staudacher.
Okajima taught a TROP2-targeting antibody-drug conjugate (ADC) of DS-1062a (abstract). Okajima taught: 1) treatment of DS-1062a was effective in TROP2-high tumor cells, but not to TROP2-low tumor cells; 2) DS-1062a was co-localized with a lysosomal marker LAMP-2 after internalizing into TROP2-high tumor cells; 3) DS-1062a exhibited strong antitumor activity with tumor regression in several TROP2-high tumors including NSCLC; 4) DS-1062a could provide a valuable therapy with a potential benefit in TROP2-expressing cancers in the clinical setting (abstract).
Staudacher taught ADCs with non-cleavable linkers have particular advantages: high stability in serum, manifest anti-tumor activity only after internalization and lysosomal degradation, and greatest anti-tumor efficacy with high and homogenous tumor expression of target antigen (page 1738, left column, second to last paragraph). Staudacher taught these ADCs do not cause bystander killing because only the tumor cells that have internalized the ADC are killed with little or no effect on surrounding, antigen-negative cells (page 1738, left column, second to last paragraph).
Regarding instant claim 5, it would have been obvious for a person having ordinary skill in the art to modify the method of Maclaren above of treating cancer that expressed CD22 comprising parenterally administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 10 mg/kg CAT-02-106 which targeted CD22, wherein subject body weight was not affected by treatment with the ADC, wherein CAT-02-106 is an anti-CD22 humanized monoclonal antibody CAT-02 with a C-terminal tagged formylglycine aldehyde tag of Leu-fGly-Thr-Pro-Ser-Arg conjugated to RED-106, wherein the aldehyde tag sequence was inserted at the heavy chain C-terminus which is the CH3, and wherein the antibody conjugated ADC had the structure
PNG
media_image4.png
259
495
media_image4.png
Greyscale
- by:
1) exchanging the anti-CD22 antibody for a CD22 expressing cancer to an anti-TACSTDS, also known as TROP2, antibody of DS-1062a for a TACSTDS, also known as TROP2, high expressing cancer in view of Bose.
This is obvious because:
1a) Okajima taught a TROP2-targeting antibody-drug conjugate (ADC) of DS-1062a, wherein: i) treatment of DS-1062a was effective in TROP2-high tumor cells, but not to TROP2-low tumor cells; ii) DS-1062a was co-localized with a lysosomal marker LAMP-2 after internalizing into TROP2-high tumor cells; iii) DS-1062a exhibited strong antitumor activity with tumor regression in several TROP2-high tumors including NSCLC; and iv) DS-1062a could provide a valuable therapy with a potential benefit in TROP2-expressing cancers in the clinical setting.
There is a reasonable expectation of success because:
1a) Okajima taught a TROP2-targeting antibody-drug conjugate (ADC) of DS-1062a, wherein: i) treatment of DS-1062a was effective in TROP2-high tumor cells, but not to TROP2-low tumor cells; ii) DS-1062a was co-localized with a lysosomal marker LAMP-2 after internalizing into TROP2-high tumor cells; iii) DS-1062a exhibited strong antitumor activity with tumor regression in several TROP2-high tumors including NSCLC; and iv) DS-1062a could provide a valuable therapy with a potential benefit in TROP2-expressing cancers in the clinical setting.
1b) Staudacher taught: i) ADCs with non-cleavable linkers have particular advantages: high stability in serum, manifest anti-tumor activity only after internalization and lysosomal degradation, and greatest anti-tumor efficacy with high and homogenous tumor expression of target antigen; and ii) these ADCs do not cause bystander killing because only the tumor cells that have internalized the ADC are killed with little or no effect on surrounding, antigen-negative cells. Thus, exchange to huDS6 with the non-cleavable linker of RED-106 would not be expected to be as toxic to surrounding tissues that express less Muc-1.
This would produce a method of Maclaren, Okajima, and Staudacher of treating cancer with high expression of TACSTD2, also known as TROP2, comprising parenterally administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 10 mg/kg anti-TACSTDS antibody of DS-1062a conjugated to 106 which targeted TACSTD2, also known as TROP2, (instant claim 5), wherein subject body weight was naturally not affected by treatment with the ADC, wherein anti-TACSTDS antibody of DS-1062a conjugated to 106 is an anti- anti-TACSTDS antibody with a formylglycine aldehyde tag of Leu-fGly-Thr-Pro-Ser-Arg conjugated to RED-106, wherein the aldehyde tag sequence was positioned in the heavy chain C-terminus, wherein the antibody conjugated ADC had the structure bound to fGly’
PNG
media_image4.png
259
495
media_image4.png
Greyscale
, wherein the method naturally reduces toxicity associated with target-mediated cross-reactivity of the administered ADC in a subject.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5-6, 9-20, and 22-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-53 and 63 of copending Application No. 18/578,690 in view of WO 2019/118411 (Maclaren A et al.), OncLive et al. (https://www.onclive.com/view/role-of-trop-2-as-an-actionable-biomarker-in-solid-tumors 2020), and Staudacher AH et al. (Br J Cancer 2017 117(12):1736-1742.) and evidenced by NCI drug Dictionary TRPH-222 (https://www.cancer.gov/ publications/dictionaries/ cancer-drug/def/anti-cd22-adc-trph-222, 2026) and Kato J et al. (Oncoimmunology. 2012 Dec 1;1(9):1469–1475).
‘690 taught compositions and methods of treatment with a conjugate of formula (II), wherein the structure is
PNG
media_image5.png
131
218
media_image5.png
Greyscale
, and wherein LA is a first linker, LB is a second linker, W11 is a drug and W13 is an anti-TACSTD2 antibody in copending claims 9-53 and 63. ‘690 taught a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a conjugate formula (II) above, wherein the administering is effective to treat cancer in the subject in copending claims 9 and 47. ‘690 taught the anti-TACSTD2 antibody is an IgG1 kappa antibody in copending claim 23. ‘690 taught the conjugate is of the formula
PNG
media_image6.png
254
427
media_image6.png
Greyscale
in copending claim 31
‘690 taught the TACSTD2 antibody comprises a sequence of L(fGly’)TPSR in copending claim 25. ‘690 taught the light chain constant region comprises the sequence KVDNAL(fGly')TPSRQSGNSQ in copending claim 34. ‘690 taught the fGly' residue is positioned in a heavy chain CH1 region of the anti-TACSTD2 antibody in copending claim 36. ‘690 taught the fGly' residue is positioned in a heavy chain CH2 region of the anti-TACSTD2 antibody in copending claim 40. ‘690 taught the fGly' residue is positioned in a heavy chain CH3 region of the anti-TACSTD2 antibody in copending claim 41. ‘690 taught the TACSTD2 antibody is positioned at a C-terminus of a heavy chain constant region in copending claim 27.
‘690 did not teach a single embodiment of a method of reducing toxicity associated with target-mediated cross-reactivity in a subject by administering an antibody-drug conjugate (ADC) of formula (I) to the subject, wherein, the ADC of formula (I) is:
PNG
media_image7.png
237
441
media_image7.png
Greyscale
, wherein W1 is an antibody binding to an antigen; and wherein the administering reduces the toxicity in the subject associated with target-mediated cross-reactivity of the ADC, but this is obvious in view of Maclaren, OncLive, and Staudacher.
The instant specification taught the methods of the present invention include a method of reducing the target-mediated cross-reactivity of an ADC in a subject, wherein this phenomenon is understood to be target-mediated cross-reactivity and as an implication of this, particularly, as a result of delivery of the drug of the ADC to healthy cells, the subject might show any or a combination of clinical indications or reactions that include but are not limited to instant Table 2 (specification, pages 32-33, [00172] and Table 2). Instant Table 2 indicates bodyweight changes as a parameter
PNG
media_image2.png
46
645
media_image2.png
Greyscale
PNG
media_image3.png
74
676
media_image3.png
Greyscale
Thus, treatment with an ADC with a bodyweight loss of <10% is a method of reducing the target-mediated cross-reactivity of an ADC in a subject. Maclaren taught a method of administration of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 6 or 20 mg/kg CAT-02-106 to a subject did not result in a bodyweight change of >10%, while 60 mg/kg resulted in a bodyweight reduction of >10% (page 21, [0074] and Fig. 20), wherein the dose was administered parenterally (page 144, [00503]). Thus, dosages of an ADC that do not diminish bodyweight >10% would reducing the target-mediated cross-reactivity of an ADC in a subject.
Regarding instant claims 1, 6, 10-11, 14-15, 19-20, 22-25, Maclaren taught an effective method of treating cancer, which is a proliferative disorder (instant claim 11), that expressed CD22 comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 10 mg/kg CAT-02-106 (page 20, [0071] and Fig. 17) which targeted CD22, wherein subject body weight was not affected by treatment with the ADC (Fig. 19). Thus, treatment with an ADC with a bodyweight loss of <10% is a method of reducing the target-mediated cross-reactivity of an ADC in a subject. Regarding the structure of CAT-02-106: i) the NCI drug Dictionary taught TRPH-222 is also known as CAT-02-106 and is a monoclonal antibody (instant claim 22) (NCI TRPH-222 page 1); and ii) Maclaren taught conjugation of a humanized (instant claim 23) anti-CD22 antibody CAT-02 to a linker maytansine payload (instant claim 24-25) via a C-terminally tagged formylglycine aldehyde tagged antibody (page 157, [00556]) wherein the linker maytansine is RED-106 (page 154, scheme and pages 156-157, [00553]), wherein the aldehyde tag is LCTPSR (SEQ ID NO: 32) with the C converted to formylglycine (instant claim 14) with formylglycine generating enzyme (FGE) (pages 142-143, [00496]) to yield Leu-fGly-Thr-Pro-Ser-Arg (instant claim 6), wherein the aldehyde tag sequence was inserted at the heavy chain C-terminus which is the CH3 (instant claim 15 and 19) (pages 142-143, [00496]), and wherein the antibody conjugated ADC had the structure
PNG
media_image4.png
259
495
media_image4.png
Greyscale
(page 118, [00432]), which would naturally have a reduced toxicity compared to when the subject is administered an ADC targeting the same antigen and comprising a linker and a payload different from the ADC of formula (I) (instant claim 10) (instant claim 1). Maclaren taught subjects are dosed parenterally with CAT-02-106 (page 162, [00565])(instant claim 20).
Regarding instant claim 26, the method of Maclaren above comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 10 mg/kg CAT-02-106 (page 20, [0071] and Fig. 17) which targeted CD22, wherein subject body weight was not affected by treatment with the ADC (Fig. 19) has a toxicity reduced in the subject by at least 2 folds when the ADC of Formula (I) is administered, as compared to administering the subject an antibody-drug conjugate targeting the same antigen and comprising a linker and a payload different from the ADC of formula (I) as evidenced by Kato. Kato taught administration of a pharmaceutical composition comprising a pharmaceutical excipient and 1 mg/kg HB22.7-SAP, which targets CD22 (Kato abstract), results in a loss of more than 10% bodyweight (Kato Fig. 3B), which is a reduced toxicity of more than 2-fold compared to CAT-02-106. Maclaren taught: an aldehyde tag can be present: i) at or near the C-terminus of an Ig heavy chain; ii) within a CH1 domain of an Ig heavy chain; iii) within a CH2 domain of an Ig heavy chain; iv) within a CH3 domain of an Ig heavy chain; v) in an Ig kappa or lambda light chain constant region (page 82, [00339]). Maclaren taught an aldehyde tag in IgG1 (page 89, [00356] and Fig. 9).
OncLive taught a low basal expression level of Trop-2 is found on the surface of multiple normal epithelial tissues, including skin and oral mucosa (page 2, second paragraph). OncLive taught Trop-2 can promote tumor growth and its overexpression is common in many types of malignant epithelial tumors (page 2, second paragraph). OncLive taught Sacituzumab govitecan-hziy is an ADC that binds to Trop-2 and delivers a potent cytotoxic drug into tumor cells (page 8, first paragraph). OncLive taught the FDA recently granted it accelerated approval for the treatment of metastatic TNBC, and it has also received fast track designation for metastatic urothelial carcinoma, NSCLC, and small cell lung cancer (page 8, first paragraph).
Staudacher taught ADCs with non-cleavable linkers have particular advantages: high stability in serum, manifest anti-tumor activity only after internalization and lysosomal degradation, and greatest anti-tumor efficacy with high and homogenous tumor expression of target antigen (page 1738, left column, second to last paragraph). Staudacher taught these ADCs do not cause bystander killing because only the tumor cells that have internalized the ADC are killed with little or no effect on surrounding, antigen-negative cells (page 1738, left column, second to last paragraph).
Regarding instant claims 1-3, 5-6, 9-20, and 22-26, it would have been obvious for a person having ordinary skill in the art to take ‘690 copending claims 9, 23, 25, 27, 31, 34, 36, 40, 41 of a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a conjugate formula (II) with the structure
PNG
media_image6.png
254
427
media_image6.png
Greyscale
, wherein the anti-TACSTD2 antibody is an IgG1 kappa antibody, wherein the TACSTD2 antibody comprises a sequence of L(fGly’)TPSR or KVDNAL(fGly')TPSRQSGNSQ positioned in : i) the light chain constant region; ii) a heavy chain CH1 region; iii) a heavy chain CH2 region; iv) a heavy chain CH3 region; or v) at a C-terminus of a heavy chain constant and modify it by:
Administering the ADC parenterally in view of Maclaren;
Using a monoclonal humanized antibody in view of Maclaren;
This is obvious because:
1a) Maclaren taught an effective method of treating cancer by administering an ADC with an fGly aldehyde tagged linker maytansine of formula (I) wherein parenteral administration and a humanized antibody were effective; and
1b) OncLive taught a low basal expression level of Trop-2 is found on the surface of multiple normal epithelial tissues, including skin and oral mucosa and a Trop-2 ADC is effective.
There is a reasonable expectation of success because:
1a) Maclaren taught an effective method of treating cancer by administering an ADC with an fGly aldehyde tagged linker maytansine of formula (I) wherein parenteral administration and a humanized antibody were effective;
1b) OncLive taught a low basal expression level of Trop-2 is found on the surface of multiple normal epithelial tissues, including skin and oral mucosa and a Trop-2 ADC is effective;
1c) Staudacher taught: i) ADCs with non-cleavable linkers have particular advantages: high stability in serum, manifest anti-tumor activity only after internalization and lysosomal degradation, and greatest anti-tumor efficacy with high and homogenous tumor expression of target antigen; and ii) these ADCs do not cause bystander killing because only the tumor cells that have internalized the ADC are killed with little or no effect on surrounding, antigen-negative cells. Thus, the TROP2 targeted ADC with the non-cleavable linker of RED-106 would not be expected to be toxic to the skin, which also expresses TROP2 but at lower levels.
This would produce a method of ‘690, Maclaren, OncLive, and Staudacher of treating cancer, which is a cell proliferative disorder (instant claim 11), that expressed TACSTD2 comprising parenterally (instant claim 20) administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a conjugate formula (II) with the structure bound to fGly’
PNG
media_image6.png
254
427
media_image6.png
Greyscale
(instant claims 24-25), wherein a humanized monoclonal anti-TACSTD2 antibody is an IgG1 kappa antibody (instant claims 12-13 and 22-23), wherein the antibody is monoclonal (instant claim 22), wherein the TACSTD2 antibody comprises a sequence of L(fGly’)TPSR or KVDNAL(fGly')TPSRQSGNSQ (instant claims 6 and 14) positioned in : i) the light chain constant region; ii) a heavy chain CH1 region; iii) a heavy chain CH2 region; iv) a heavy chain CH3 region; or v) at a C-terminus of a heavy chain constant (instant claims 15-19), wherein the antibody targeted TACSTD2 (instant claims 3 and 5), which is expressed in skin (instant claim 2) which is a vital organ (instant claim 9), wherein subject body weight or skin was naturally not affected by treatment with the ADC, wherein the ADC above is an anti-TACSTD2 antibody with a formylglycine aldehyde tag of Leu-fGly-Thr-Pro-Ser-Arg conjugated to RED-106, wherein the aldehyde tag sequence was positioned in the heavy chain C-terminus, and wherein the antibody conjugated ADC had the structure
PNG
media_image4.png
259
495
media_image4.png
Greyscale
, and wherein the method naturally reduces toxicity associated with target-mediated cross-reactivity of the administered ADC in a subject (instant claim 1), wherein the toxicity is naturally reduced at least two-fold compared to when the subject is administered a higher dose of an ADC targeting the same antigen and comprising a linker and a payload different from the ADC of formula (I) (instant claim 10 and 26).
This is a provisional nonstatutory double patenting rejection.
Claims 1, 10-11, and 24-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. US 12,102,689.
‘689 taught a conjugate that includes one modified amino acid residue side chain of formula (I):
PNG
media_image8.png
264
542
media_image8.png
Greyscale
wherein W2 is an anti-CD22 antibody in copending claim 1. ‘689 taught a method of treating leukemia or a lymphoma in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a conjugate of patented claim 1, wherein the administering is effective to treat cancer in the subject in patented claim 21.
The instant specification taught the methods of the present invention include a method of reducing the target-mediated cross-reactivity of an ADC in a subject, wherein this phenomenon is understood to be target-mediated cross-reactivity and as an implication of this, particularly, as a result of delivery of the drug of the ADC to healthy cells, the subject might show any or a combination of clinical indications or reactions that include but are not limited to instant Table 2 (specification, pages 32-33, [00172] and Table 2). Instant Table 2 indicates bodyweight changes as a parameter
PNG
media_image2.png
46
645
media_image2.png
Greyscale
PNG
media_image3.png
74
676
media_image3.png
Greyscale
Thus, treatment with an ADC with a bodyweight loss of <10% is a method of reducing the target-mediated cross-reactivity of an ADC in a subject. Maclaren taught a method of administration of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 6 or 20 mg/kg CAT-02-106 to a subject did not result in a bodyweight change of >10%, while 60 mg/kg resulted in a bodyweight reduction of >10% (page 21, [0074] and Fig. 20), wherein the dose was administered parenterally (page 144, [00503]). Thus, dosages of an ADC that do not diminish bodyweight >10% would reducing the target-mediated cross-reactivity of an ADC in a subject.
Thus, the method of patented claim 21 and 1 anticipate the active method steps of instant claims 1, 10-11, and 24-26.
Claims 1, 6, 10-20, and 22-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. US 12,102,689 in view of WO 2019/118411 (Maclaren A et al.), WO 2015/187428 (Rabuka D et al.), and Staudacher AH et al. (Br J Cancer 2017 117(12):1736-1742.) and evidenced by NCI drug Dictionary TRPH-222 (https://www.cancer.gov/ publications/dictionaries/cancer-drug/def/anti-cd22-adc-trph-222, 2026) and Kato J et al. (Oncoimmunology. 2012 Dec 1;1(9):1469–1475).
‘689 taught a conjugate that includes one modified amino acid residue side chain of formula (I):
PNG
media_image8.png
264
542
media_image8.png
Greyscale
wherein W2 is an anti-CD22 antibody in copending claim 1, wherein the antiCD22 antibody contains the sequence L(fGly’)TPSR in patented claim 3, wherein the modified amino acid is positioned at a C-terminus of a heavy chain constant region of the antibody in patented claim 5, wherein the modified amino acid is positioned in a light chain constant region of the antibody in patented claim 9, wherein the light chain constant region comprises KVDNAL(fGly’)TPSRQSGNSQ in patented claim 11, wherein the modified amino acid is positioned in a heavy chain constant region CH1 of the antibody in copending claim 13, wherein the modified amino acid is positioned in a heavy chain constant region CH2 of the antibody in copending patented claim 17, wherein the modified amino acid is positioned in a heavy chain constant region CH3 of the antibody in patented claim 18. ‘689 taught a method of treating leukemia or a lymphoma in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a conjugate of patented claim 1, wherein the administering is effective to treat cancer in the subject in patented claim 21.
‘689 did not teach a single embodiment of a method of reducing toxicity associated with target-mediated cross-reactivity in a subject by administering an antibody-drug conjugate (ADC) of formula (I) to the subject, wherein, the ADC of formula (I) is:
PNG
media_image7.png
237
441
media_image7.png
Greyscale
, wherein W1 is an antibody binding to an antigen; and wherein the administering reduces the toxicity in the subject associated with target-mediated cross-reactivity of the ADC, wherein: 1) the location of the antibody binding to fGly is identified; 2) the ADC is administered parenterally; 3) the antibody is a monoclonal humanized IgG1 kappa antibody, but this is obvious in view of Maclaren, Rabuka, and Staudacher.
The instant specification taught the methods of the present invention include a method of reducing the target-mediated cross-reactivity of an ADC in a subject, wherein this phenomenon is understood to be target-mediated cross-reactivity and as an implication of this, particularly, as a result of delivery of the drug of the ADC to healthy cells, the subject might show any or a combination of clinical indications or reactions that include but are not limited to instant Table 2 (specification, pages 32-33, [00172] and Table 2). Instant Table 2 indicates bodyweight changes as a parameter
PNG
media_image2.png
46
645
media_image2.png
Greyscale
PNG
media_image3.png
74
676
media_image3.png
Greyscale
Thus, treatment with an ADC with a bodyweight loss of <10% is a method of reducing the target-mediated cross-reactivity of an ADC in a subject. Maclaren taught a method of administration of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 6 or 20 mg/kg CAT-02-106 to a subject did not result in a bodyweight change of >10%, while 60 mg/kg resulted in a bodyweight reduction of >10% (page 21, [0074] and Fig. 20), wherein the dose was administered parenterally (page 144, [00503]). Thus, dosages of an ADC that do not diminish bodyweight >10% would reducing the target-mediated cross-reactivity of an ADC in a subject.
Regarding instant claims 1, 6, 10-11, 14-15, 19-20, 22-25, Maclaren taught an effective method of treating cancer, which is a proliferative disorder (instant claim 11), that expressed CD22 comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 10 mg/kg CAT-02-106 (page 20, [0071] and Fig. 17) which targeted CD22, wherein subject body weight was not affected by treatment with the ADC (Fig. 19). Thus, treatment with an ADC with a bodyweight loss of <10% is a method of reducing the target-mediated cross-reactivity of an ADC in a subject. Regarding the structure of CAT-02-106: i) the NCI drug Dictionary taught TRPH-222 is also known as CAT-02-106 and is a monoclonal antibody (instant claim 22) (NCI TRPH-222 page 1); and ii) Maclaren taught conjugation of a humanized (instant claim 23) anti-CD22 antibody CAT-02 to a linker maytansine payload (instant claim 24-25) via a C-terminally tagged formylglycine aldehyde tagged antibody (page 157, [00556]) wherein the linker maytansine is RED-106 (page 154, scheme and pages 156-157, [00553]), wherein the aldehyde tag is LCTPSR (SEQ ID NO: 32) with the C converted to formylglycine (instant claim 14) with formylglycine generating enzyme (FGE) (pages 142-143, [00496]) to yield Leu-fGly-Thr-Pro-Ser-Arg (instant claim 6), wherein the aldehyde tag sequence was inserted at the heavy chain C-terminus which is the CH3 (instant claim 15 and 19) (pages 142-143, [00496]), and wherein the antibody conjugated ADC had the structure
PNG
media_image4.png
259
495
media_image4.png
Greyscale
(page 118, [00432]), which would naturally have a reduced toxicity compared to when the subject is administered an ADC targeting the same antigen and comprising a linker and a payload different from the ADC of formula (I) (instant claim 10) (instant claim 1). Maclaren taught subjects are dosed parenterally with CAT-02-106 (page 162, [00565])(instant claim 20). Maclaren taught: an aldehyde tag can be present: i) at or near the C-terminus of an Ig heavy chain; ii) within a CH1 domain of an Ig heavy chain; iii) within a CH2 domain of an Ig heavy chain; iv) within a CH3 domain of an Ig heavy chain; v) in an Ig kappa or lambda light chain constant region (page 82, [00339]). Maclaren taught an aldehyde tag in IgG1 (page 89, [00356] and Fig. 9). Regarding instant claim 26, the method of Maclaren above comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 10 mg/kg CAT-02-106 (page 20, [0071] and Fig. 17) which targeted CD22, wherein subject body weight was not affected by treatment with the ADC (Fig. 19) has a toxicity reduced in the subject by at least 2 folds when the ADC of Formula (I) is administered, as compared to administering the subject an antibody-drug conjugate targeting the same antigen and comprising a linker and a payload different from the ADC of formula (I) as evidenced by Kato. Kato taught administration of a pharmaceutical composition comprising a pharmaceutical excipient and 1 mg/kg HB22.7-SAP, which targets CD22 (Kato abstract), results in a loss of more than 10% bodyweight (Kato Fig. 3B), which is a reduced toxicity of more than 2-fold compared to CAT-02-106.
Rabuka taught the aldehyde tags in trastuzumab and cloned into the constant regions of a prototype human IgG1 heavy chain and kappa light chain wherein the aldehyde tag was well-tolerated when inserted into a variety of locations along the antibody backbone and the tagged antibodies showed no to very little aggregation in: a light chain constant region after A153 (LC); heavy chain CH1 region after G118; and heavy chain CH2 region after N344 in the antibody (pages 144-145, [00436-00438] and Table 2).Rabuka taught the unconjugated and ADC versions of LC-, CH1-, and CT-tagged antibodies were poorly immunogenic (pages 147-148, [00443] and Table 5). Rabuka taught administration of a pharmaceutical composition comprising anti-HER2 ADCs conjugated via aldehyde tags at different locations within the antibody such as CH1, LC, and the C terminal were effective at treating HER2 positive cancer (Fig. 11A).
Staudacher taught ADCs with non-cleavable linkers have particular advantages: high stability in serum, manifest anti-tumor activity only after internalization and lysosomal degradation, and greatest anti-tumor efficacy with high and homogenous tumor expression of target antigen (page 1738, left column, second to last paragraph). Staudacher taught these ADCs do not cause bystander killing because only the tumor cells that have internalized the ADC are killed with little or no effect on surrounding, antigen-negative cells (page 1738, left column, second to last paragraph).
Regarding instant claims 1, 6, 10-20, and 22-26, it would have been obvious for a person having ordinary skill in the art to take ‘689 patented claims 1, 3, 5, 9, 11, 13, 17-18, and 21 of a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a conjugate formula (II) with the structure
PNG
media_image6.png
254
427
media_image6.png
Greyscale
, wherein the anti-TACSTD2 antibody is an IgG1 kappa antibody, wherein the TACSTD2 antibody comprises a sequence of L(fGly’)TPSR or KVDNAL(fGly')TPSRQSGNSQ positioned in : i) the light chain constant region; ii) a heavy chain CH1 region; iii) a heavy chain CH2 region; iv) a heavy chain CH3 region; or v) at a C-terminus of a heavy chain constant and modify it by:
Administering the ADC parenterally in view of Maclaren and Rabuka;
Using a monoclonal humanized antibody in view of Maclaren and Rabuka;
Using a IgG1 kappa antibody in view of Maclaren and Rabuka;
This is obvious because:
1a) Maclaren taught an effective method of treating cancer by administering an ADC with an fGly aldehyde tagged linker maytansine of formula (I) wherein parenteral administration and a humanized antibody were effective; and
1b) Maclaren taught: an aldehyde tag can be present in an Ig kappa or lambda light chain constant region and in IgG1;
1c) Rabuka taught the aldehyde tags in trastuzumab and cloned into the constant regions of a prototype human IgG1 heavy chain and kappa light chain wherein the aldehyde tag was well-tolerated when inserted into a variety of locations along the antibody backbone and the tagged antibodies showed no to very little aggregation in: a light chain constant region after A153 (LC); heavy chain CH1 region after G118; and heavy chain CH2 region after N344 in the antibody; and
1d) Rabuka taught the unconjugated and ADC versions of LC-, CH1-, and CT-tagged antibodies were poorly immunogenic and administration of a pharmaceutical composition comprising anti-HER2 ADCs conjugated via aldehyde tags at different locations within the antibody such as CH1, LC, and the C terminal were effective at treating HER2 positive cancer.
There is a reasonable expectation of success because:
1a) Rabuka taught the aldehyde tags in trastuzumab and cloned into the constant regions of a prototype human IgG1 heavy chain and kappa light chain wherein the aldehyde tag was well-tolerated when inserted into a variety of locations along the antibody backbone and the tagged antibodies showed no to very little aggregation in: a light chain constant region after A153 (LC); heavy chain CH1 region after G118; and heavy chain CH2 region after N344 in the antibody; and
1b) Rabuka taught the unconjugated and ADC versions of LC-, CH1-, and CT-tagged antibodies were poorly immunogenic and administration of a pharmaceutical composition comprising anti-HER2 ADCs conjugated via aldehyde tags at different locations within the antibody such as CH1, LC, and the C terminal were effective at treating HER2 positive cancer.
Thus, a trastuzumab aldehyde tag conjugated ADC at these positions would be expected to be effective.
1c) Staudacher taught: i) ADCs with non-cleavable linkers have particular advantages: high stability in serum, manifest anti-tumor activity only after internalization and lysosomal degradation, and greatest anti-tumor efficacy with high and homogenous tumor expression of target antigen; and ii) these ADCs do not cause bystander killing because only the tumor cells that have internalized the ADC are killed with little or no effect on surrounding, antigen-negative cells. Thus, exchange to the anti-HER2 antibody with the non-cleavable linker of RED-106 would not be expected to be as toxic to surrounding tissues that express less HER2.
This would produce a method of ‘689, Maclaren, Rabuka, and Staudacher of treating a leukemia or lymphoma, which is a cell proliferative disorder (instant claim 11), that expressed CD22 comprising parenterally (instant claim 20) administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a conjugate formula (II) with the structure bound to fGly’
PNG
media_image6.png
254
427
media_image6.png
Greyscale
(instant claims 24-25), wherein a humanized monoclonal CD22 antibody is an IgG1 kappa antibody (instant claims 12-13 and 22-23), wherein the antibody is monoclonal (instant claim 22), wherein the CD22 antibody comprises a sequence of L(fGly’)TPSR or KVDNAL(fGly')TPSRQSGNSQ (instant claims 6 and 14) positioned in : i) the light chain constant region; ii) a heavy chain CH1 region; iii) a heavy chain CH2 region; iv) a heavy chain CH3 region; or v) at a C-terminus of a heavy chain constant (instant claims 15-19), wherein the antibody targeted CD22, wherein subject body weight is not naturally not affected by treatment with the ADC, wherein the ADC above is an anti-CD22 antibody with a formylglycine aldehyde tag of Leu-fGly-Thr-Pro-Ser-Arg conjugated to RED-106, wherein the aldehyde tag sequence was positioned in the heavy chain C-terminus, and wherein the antibody conjugated ADC had the structure
PNG
media_image4.png
259
495
media_image4.png
Greyscale
, and wherein the method naturally reduces toxicity associated with target-mediated cross-reactivity of the administered ADC in a subject (instant claim 1), wherein the toxicity is naturally reduced at least two-fold compared to when the subject is administered a higher dose of an ADC targeting the same antigen and comprising a linker and a payload different from the ADC of formula (I) (instant claim 10 and 26).
Conclusion
All claims are rejected
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN J SKOKO III whose telephone number is (571)272-1107. The examiner can normally be reached M-F 8:30 - 5:00.
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, Julie Z Wu can be reached at (571)272-5205. 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.
/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
Prosecution Insights