DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The rejections under section 103 withdrawn in favor of the following new grounds of rejection, which were necessitated by Applicant’s amendments:
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.
Claims 1, 3, 7-9, 12, 14, 15 are rejected under 35 U.S.C. 103 as being unpatentable over Cui et al., Blood (2013) 122 (21): 1637 (Cui) as evidenced by WO 2019122447 (WO 447) in view of:
Jain et al., Pharm Res (2015) 32:3526–3540 (Jain); in further view of
Chen et al., Determination of Drug-to-Antibody Ratio for Antibody-Drug Conjugates Purified from Serum, Agilent Technologies, pp. 1-9, 2016 (Agilent) and Diamantis et al., British Journal of Cancer (2016) 114, 362–367 (hereinafter “Diamantis”).
Cui teaches that ROR1 has restricted expression on human malignancies, we have generated a series of monoclonal antibodies (mAb) against the extracellular domain of human ROR1 and are advancing a lead candidate mAb UC-961 (cirmtuzumab) into human clinical trials. Cui teaches a conjugate that is anti-ROR1 Cirmtuzumab stably bound to a modified monomethyl auristatin E (MMAE) through a light chain, constant region, lysine-linker with an antibody-drug ratio (ADR) of 2.5 (designated UC-961ADC3).
WO 447 teaches that UC-961 is the instant antibody with Heavy Chain SEQ ID NO: 98 and Light Chain SEQ ID NO: 99 corresponding to the instant Heavy and Light Chains SEQ ID NOS: 1 and 2, respectively, see page 65.
Cui may fail to teach the instant linkers required by the claims. However, Jain demonstrates that MC-VC-PAB-MMAE is a common linker payload group, which is commonly used since it is protease-active and effective in cancer treatment:
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In this way, those of ordinary skill could have applied this linker-drug in the manner required and in a predictable fashion for the purposes of obtaining the recited antibody-drug conjugate (ADC). As outlined above, the primary references teach ROR1 as a target for cancer immunotherapy. Cui also teaches anti-ROR1 antibody-drug conjugates comprising Cirmtuzumab (UC-961) stably bound to auristatin E (MMAE). Jain is added for the proposition that MC-VC-PAB is applicable to these conjugates. Specifically, Jain teaches that the particular known technique of using MC-VC-PAB was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to conjugates targeting ROR1, such as Cirmtuzumab would have yielded predictable results. Accordingly, conjugating MC-VC-PAB-MMAE to UC-961) would have been prima facie obvious.
The claims also require effective amounts and regimens. However, the amount of the recited conjugate as an effective dose is a result-effective parameter that will affect the pharmacological and pharmacokinetic properties of the final composition. In this manner, the amount of a specific ingredient in a composition is clearly a result-effective parameter that a person of ordinary skill in the art would routinely optimize.
Specifically, it would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve a desired result. For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, usually rats, rabbits, dogs, or pigs. The animal model also can be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
Therapeutic efficacy and toxicity, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population), can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED5o. Pharmaceutical compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active ingredient or to maintain the desired effect. Factors which can be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions can be administered once or twice daily every 3 to 4 days, every week, or once every two weeks depending on the half-life and clearance rate of the particular formulation.
Normal dosage amounts can vary from micrograms to 100,000 micrograms, up to a maximum total dose, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
In this way, optimization of these parameters is a routine practice, and consequently, would be prima facie obvious, absent factual evidence demonstrating an unexpected benefit of the claimed amount(s).
Those of ordinary skill would have a reasonable expectation that the conjugate can treat the recited cancer since Cui teaches cytotoxic activity of each of the various cirmtuzumab-ADC against ROR1 on human malignancies.
Any observed pharmacological effects (see claim 15 and 16 i.e., eradication) would have been a necessary aspect of the conjugates, see MPEP 2112.01 (“Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”).
WO 447 teaches that UC-961, as disclosed by Cui is the instant antibody with Heavy Chain SEQ ID NO: 98 and Light Chain SEQ ID NO: 99 corresponding to the instant Heavy and Light Chains SEQ ID NOS: 1 and 2, respectively, see page 65. Therefore, CUI is enabling for the instant ADC.
With regard to DAR, there are a limited and finite number of DAR’s for a given antibody- drug conjugate (ADC), around 8. Optimization of the DAR is a critical part of ADC development, since the DAR value affects the efficacy of the drug, as low drug loading reduces the potency, while high drug loading can negatively affect pharmacokinetics (PK)1 and toxicity. At the time the invention was made, easy, accurate and reproducible DAR calculation of ADC’s was within the purview of those of ordinary skill, see Agilent:
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In this manner, it would have been obvious to one have ordinary skill in the art at the time that applicant’s inventions was made to have made ADC’s with the recited DAR with a reasonable expectation that the resulting ADC with a DAR within the claimed range would be useful in treating cancer. In this connection, it is well-settled that ADC’s with a DAR from 1-8 are well within the purview of those of ordinary skill; and it would have been obvious to one of ordinary skill in the art at the time the invention was made to choose from this finite number of DAR options with a reasonable expectation of success of producing a ADC functional with a functional DAR.
Specifically, it is well within the skill of the artisan to try any of the 1-8 DAR’s. As outlined above, a DAR value affects the efficacy of the drug, as low drug loading reduces the potency, while high drug loading can negatively affect pharmacokinetics (PK)1 and toxicity. Here, a skilled chemist at the time would simply make the known ADC’s of the known 8 DAR’s. Indeed, it would have been part and parcel to make the different DAR’s to find one that is pharmaceutically acceptable.
With regard to any unpredictability associated with the DAR’s, the notion that unpredictability confers patentability in cases of DAR’s of known ADC’s should be disregarded since a rule of law equating unpredictability to patentability, applied in this case, would mean that any new ADC based on a different DAR would be separately patentable, simply because the formation and properties of each ADC must be verified through testing. This cannot be the proper standard since the expectation of success need only be reasonable, not absolute.
Here, the references provide the reasonable expectation of success, as outlined above. Namely, the references demonstrate the reasonable expectation of success since the references sufficiently characterize the instant ADC’s including the required heavy and light chains, i.e. (SEQ ID NO’s), conjugated to MMAE via a val/cit linker. Again, the expectation of success need only be reasonable, as it is here, and not absolute, (“obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).”).
Rather, Applicant has conducted a common optimization of the known DAR’s to produce the claimed ADC, which is routine. Specifically, Applicant engaged in routine, verification testing to optimize selection of one of several known and clearly suggested DAR’s to prepare a pharmaceutically-acceptable conjugate. In this regard, creating a “product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient . . . to enhance commercial opportunities . . . is universal—and even common-sensical.” see DyStar Textilfarben GmbH v. C.H. Patrick Co., 464 F.3d 1356 at 1368.
The rejected claims cover treatment DLBCL and MCL or not specifically taught by the references. However, antibody-drug conjugates (ADCs) offer benefits in cancer therapy beyond traditional chemo-, hormone- and immune checkpoint-therapies by selectively targeting cancer cells and delivering potent cytotoxic drugs directly to cancer cells, increasing effectiveness and reducing side effects compared to traditional chemotherapy. This targeted delivery improves the "therapeutic index" by increasing drug concentration in the tumor while decreasing it in healthy tissues, see Diamantis (“Antibody-drug conjugates (ADCs) are an emerging novel class of anticancer treatment agents that combines the selectivity of targeted treatment with the cytotoxic potency of chemotherapy drugs. New linker technology associated with novel highly potent cytotoxic payloads has permitted the development of more effective and safe ADCs. In recent years, two ADCs have been licensed, T-DM1 and brentuximab vedotin, and are already establishing their place in cancer treatment. A plethora of ADCs are being investigated in phases I and II trials, emerging data of which appears promising. As we deepen our understanding of what makes a successful ADC, an increasing number of ADCs will likely become viable treatment options as single agents or in combination with chemotherapy. This review will present the philosophy underlying ADCs, their main characteristics and current research developments with a focus on ADCs in solid tumours.”).
In this way, those of ordinary skill could have applied the instant ADC’s in the manner required and in a predictable fashion for the purposes of treating DLBCL and MCL. As discussed above, Diamantis is added for the proposition that ADC’s are applicable to treating the recited cancers. Specifically, Diamantis teaches the particular known technique of using ADC’s an alternate therapy for treating cancers was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to the recited cancers would have yielded predictable results. Accordingly, using the instant ADC’s to treat DLBCL and MCL would have been prima facie obvious.
Claims 1, 3, 7-9, 12, 14, 15 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018237335 (WO 335) in view of Chen et al., Determination of Drug-to-Antibody Ratio for Antibody-Drug Conjugates Purified from Serum, Agilent Technologies, pp. 1-9, 2016 (Agilent) and Diamantis et al., British Journal of Cancer (2016) 114, 362–367 (hereinafter “Diamantis”).
WO 335 describes in example 1 (paragraph [0157]) an immunoconjugate ADC-A resulting from the conjugation of Ab1 with MC-VC-PAB-MMAE, the average DAR being 3.89-5.09. According to Table 1, Ab1 contains SEQ ID NO:3 (which corresponds to SEQ ID NO: 1 of the present application) as the heavy chain (HC) and SEQ ID NO:4 (which corresponds to SEQ ID NO: 2 of the present application) as the light chain (LC). MC-VC-PAB-MMAE is shown in Figure 1 to be similar to the claimed drug moiety of formula (I). In example 8 (paragraphs [0184]-[0196] it is described that ADC-A was administered intravenously in doses of 1, 2 (and 5) mg/kg for the treatment of various cancers (T-cell leukemia, MCL (mantle cell lymphoma), germinal center B-cell like diffuse large B cell lymphoma, Richter's syndrome, human triple negative breast cancer etc (i.e. hematological cancers, solid tumors). It is mentioned that the tumor was completely eradicated (paragraph [0194]). The embodiment of previously treated cancer that has relapsed is described at paragraph [0204].
WO 335 also discloses in example 8 (paragraphs [0184]-[0196]) a weekly dose was given for a total of 4 doses, i.e. on days 1, 8, 15 and 22; a q4d dosing regimen (every 4 days) and in table 11 a dosing regimen is proposed for every 2 weeks for 3-5 administrations and every 4 weeks thereafter.
Nonetheless, the amount of the recited conjugate as an effective dose is a result-effective parameter that will affect the pharmacological and pharmacokinetic properties of the final composition. In this manner, the amount of a specific ingredient in a composition is clearly a result-effective parameter that a person of ordinary skill in the art would routinely optimize.
Specifically, it would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve a desired result. For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, usually rats, rabbits, dogs, or pigs. The animal model also can be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
Therapeutic efficacy and toxicity, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population), can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED5o. Pharmaceutical compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active ingredient or to maintain the desired effect. Factors which can be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions can be administered once or twice daily every 3 to 4 days, every week, or once every two weeks depending on the half-life and clearance rate of the particular formulation.
Normal dosage amounts can vary from micrograms to 100,000 micrograms, up to a maximum total dose, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
In this way, optimization of these parameters is a routine practice, and consequently, would be prima facie obvious, absent factual evidence demonstrating an unexpected benefit of the claimed amount(s).
Those of ordinary skill would have a reasonable expectation that the conjugate can treat the recited cancer since ROR1 is expressed on human malignancies.
Any observed pharmacological effects (see claim 15 and 16 i.e., eradication) would have been a necessary aspect of the conjugates, see MPEP 2112.01 (“Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”).
With regard to DAR, there are a limited and finite number of DAR’s for a given antibody- drug conjugate (ADC), around 8. Optimization of the DAR is a critical part of ADC development, since the DAR value affects the efficacy of the drug, as low drug loading reduces the potency, while high drug loading can negatively affect pharmacokinetics (PK)1 and toxicity. At the time the invention was made, easy, accurate and reproducible DAR calculation of ADC’s was within the purview of those of ordinary skill, see Agilent:
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In this manner, it would have been obvious to one have ordinary skill in the art at the time that applicant’s inventions was made to have made ADC’s with the recited DAR with a reasonable expectation that the resulting ADC with a DAR within the claimed range would be useful in treating cancer. In this connection, it is well-settled that ADC’s with a DAR from 1-8 are well within the purview of those of ordinary skill; and it would have been obvious to one of ordinary skill in the art at the time the invention was made to choose from this finite number of DAR options with a reasonable expectation of success of producing a ADC functional with a functional DAR.
Specifically, it is well within the skill of the artisan to try any of the 1-8 DAR’s. As outlined above, a DAR value affects the efficacy of the drug, as low drug loading reduces the potency, while high drug loading can negatively affect pharmacokinetics (PK)1 and toxicity. Here, a skilled chemist at the time would simply make the known ADC’s of the known 8 DAR’s. Indeed, it would have been part and parcel to make the different DAR’s to find one that is pharmaceutically acceptable.
With regard to any unpredictability associated with the DAR’s, the notion that unpredictability confers patentability in cases of DAR’s of known ADC’s should be disregarded since a rule of law equating unpredictability to patentability, applied in this case, would mean that any new ADC based on a different DAR would be separately patentable, simply because the formation and properties of each ADC must be verified through testing. This cannot be the proper standard since the expectation of success need only be reasonable, not absolute.
Here, the references provide the reasonable expectation of success, as outlined above. Namely, the references demonstrate the reasonable expectation of success since the references sufficiently characterize the instant ADC’s including the required heavy and light chains, i.e. (SEQ ID NO’s), conjugated to MMAE via a val/cit linker. Again, the expectation of success need only be reasonable, as it is here, and not absolute, (“obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).”).
Rather, Applicant has conducted a common optimization of the known DAR’s to produce the claimed ADC, which is routine. Specifically, Applicant engaged in routine, verification testing to optimize selection of one of several known and clearly suggested DAR’s to prepare a pharmaceutically-acceptable conjugate. In this regard, creating a “product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient . . . to enhance commercial opportunities . . . is universal—and even common-sensical.” see DyStar Textilfarben GmbH v. C.H. Patrick Co., 464 F.3d 1356 at 1368.
The rejected claims cover treatment DLBCL and MCL or not specifically taught by the references. However, antibody-drug conjugates (ADCs) offer benefits in cancer therapy beyond traditional chemo-, hormone- and immune checkpoint-therapies by selectively targeting cancer cells and delivering potent cytotoxic drugs directly to cancer cells, increasing effectiveness and reducing side effects compared to traditional chemotherapy. This targeted delivery improves the "therapeutic index" by increasing drug concentration in the tumor while decreasing it in healthy tissues, see Diamantis (“Antibody-drug conjugates (ADCs) are an emerging novel class of anticancer treatment agents that combines the selectivity of targeted treatment with the cytotoxic potency of chemotherapy drugs. New linker technology associated with novel highly potent cytotoxic payloads has permitted the development of more effective and safe ADCs. In recent years, two ADCs have been licensed, T-DM1 and brentuximab vedotin, and are already establishing their place in cancer treatment. A plethora of ADCs are being investigated in phases I and II trials, emerging data of which appears promising. As we deepen our understanding of what makes a successful ADC, an increasing number of ADCs will likely become viable treatment options as single agents or in combination with chemotherapy. This review will present the philosophy underlying ADCs, their main characteristics and current research developments with a focus on ADCs in solid tumours.”).
In this way, those of ordinary skill could have applied the instant ADC’s in the manner required and in a predictable fashion for the purposes of treating DLBCL and MCL. As discussed above, Diamantis is added for the proposition that ADC’s are applicable to treating the recited cancers. Specifically, Diamantis teaches the particular known technique of using ADC’s an alternate therapy for treating cancers was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to the recited cancers would have yielded predictable results. Accordingly, using the instant ADC’s to treat DLBCL and MCL would have been prima facie obvious.
Claims 1, 3, 7-9, 12, 14, 15 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Publication No. 20200030454 based on an application by Lannutti et al. (Lannutti) in view of Chen et al., Determination of Drug-to-Antibody Ratio for Antibody-Drug Conjugates Purified from Serum, Agilent Technologies, pp. 1-9, 2016 (Agilent) and Diamantis et al., British Journal of Cancer (2016) 114, 362–367 (hereinafter “Diamantis”).
Lannutti teaches the recited conjugates:
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Lannutti also teaches the instant ant-ROR1 antibody:
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wherein Heavy Chain SEQ ID NO: 3 and Light Chain SEQ ID NO: 4 correspond to the instant Heavy and Light Chains SEQ ID NOS: 1 and 2, respectively
Lannutti may not explicitly teach the instant effective amounts and regimens. Nonetheless, the amount of the recited conjugate as an effective dose is a result-effective parameter that will affect the pharmacological and pharmacokinetic properties of the final composition. In this manner, the amount of a specific ingredient in a composition is clearly a result-effective parameter that a person of ordinary skill in the art would routinely optimize.
Specifically, it would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve a desired result. For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, usually rats, rabbits, dogs, or pigs. The animal model also can be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
Therapeutic efficacy and toxicity, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population), can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED5o. Pharmaceutical compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active ingredient or to maintain the desired effect. Factors which can be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions can be administered once or twice daily every 3 to 4 days, every week, or once every two weeks depending on the half-life and clearance rate of the particular formulation.
Normal dosage amounts can vary from micrograms to 100,000 micrograms, up to a maximum total dose, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
In this way, optimization of these parameters is a routine practice, and consequently, would be prima facie obvious, absent factual evidence demonstrating an unexpected benefit of the claimed amount(s).
Those of ordinary skill would have a reasonable expectation that the conjugate can treat the recited cancer since ROR1 is expressed on human malignancies.
Any observed pharmacological effects (see claim 15 and 16 i.e., eradication) would have been a necessary aspect of the conjugates, see MPEP 2112.01 (“Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”).
With regard to DAR, there are a limited and finite number of DAR’s for a given antibody- drug conjugate (ADC), around 8. Optimization of the DAR is a critical part of ADC development, since the DAR value affects the efficacy of the drug, as low drug loading reduces the potency, while high drug loading can negatively affect pharmacokinetics (PK)1 and toxicity. At the time the invention was made, easy, accurate and reproducible DAR calculation of ADC’s was within the purview of those of ordinary skill, see Agilent:
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In this manner, it would have been obvious to one have ordinary skill in the art at the time that applicant’s inventions was made to have made ADC’s with the recited DAR with a reasonable expectation that the resulting ADC with a DAR within the claimed range would be useful in treating cancer. In this connection, it is well-settled that ADC’s with a DAR from 1-8 are well within the purview of those of ordinary skill; and it would have been obvious to one of ordinary skill in the art at the time the invention was made to choose from this finite number of DAR options with a reasonable expectation of success of producing a ADC functional with a functional DAR.
Specifically, it is well within the skill of the artisan to try any of the 1-8 DAR’s. As outlined above, a DAR value affects the efficacy of the drug, as low drug loading reduces the potency, while high drug loading can negatively affect pharmacokinetics (PK)1 and toxicity. Here, a skilled chemist at the time would simply make the known ADC’s of the known 8 DAR’s. Indeed, it would have been part and parcel to make the different DAR’s to find one that is pharmaceutically acceptable.
With regard to any unpredictability associated with the DAR’s, the notion that unpredictability confers patentability in cases of DAR’s of known ADC’s should be disregarded since a rule of law equating unpredictability to patentability, applied in this case, would mean that any new ADC based on a different DAR would be separately patentable, simply because the formation and properties of each ADC must be verified through testing. This cannot be the proper standard since the expectation of success need only be reasonable, not absolute.
Here, the references provide the reasonable expectation of success, as outlined above. Namely, the references demonstrate the reasonable expectation of success since the references sufficiently characterize the instant ADC’s including the required heavy and light chains, i.e. (SEQ ID NO’s), conjugated to MMAE via a val/cit linker. Again, the expectation of success need only be reasonable, as it is here, and not absolute, (“obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).”).
Rather, Applicant has conducted a common optimization of the known DAR’s to produce the claimed ADC, which is routine. Specifically, Applicant engaged in routine, verification testing to optimize selection of one of several known and clearly suggested DAR’s to prepare a pharmaceutically-acceptable conjugate. In this regard, creating a “product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient . . . to enhance commercial opportunities . . . is universal—and even common-sensical.” see DyStar Textilfarben GmbH v. C.H. Patrick Co., 464 F.3d 1356 at 1368.
The rejected claims cover treatment DLBCL and MCL or not specifically taught by the references. However, antibody-drug conjugates (ADCs) offer benefits in cancer therapy beyond traditional chemo-, hormone- and immune checkpoint-therapies by selectively targeting cancer cells and delivering potent cytotoxic drugs directly to cancer cells, increasing effectiveness and reducing side effects compared to traditional chemotherapy. This targeted delivery improves the "therapeutic index" by increasing drug concentration in the tumor while decreasing it in healthy tissues, see Diamantis (“Antibody-drug conjugates (ADCs) are an emerging novel class of anticancer treatment agents that combines the selectivity of targeted treatment with the cytotoxic potency of chemotherapy drugs. New linker technology associated with novel highly potent cytotoxic payloads has permitted the development of more effective and safe ADCs. In recent years, two ADCs have been licensed, T-DM1 and brentuximab vedotin, and are already establishing their place in cancer treatment. A plethora of ADCs are being investigated in phases I and II trials, emerging data of which appears promising. As we deepen our understanding of what makes a successful ADC, an increasing number of ADCs will likely become viable treatment options as single agents or in combination with chemotherapy. This review will present the philosophy underlying ADCs, their main characteristics and current research developments with a focus on ADCs in solid tumours.”).
In this way, those of ordinary skill could have applied the instant ADC’s in the manner required and in a predictable fashion for the purposes of treating DLBCL and MCL. As discussed above, Diamantis is added for the proposition that ADC’s are applicable to treating the recited cancers. Specifically, Diamantis teaches the particular known technique of using ADC’s an alternate therapy for treating cancers was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to the recited cancers would have yielded predictable results. Accordingly, using the instant ADC’s to treat DLBCL and MCL would have been prima facie obvious.
Claims 1, 3, 7-9, 12, 14, 15 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Publication No. 20220133901 based on an application by Lannutti et al. (Lannutti II) in view of Chen et al., Determination of Drug-to-Antibody Ratio for Antibody-Drug Conjugates Purified from Serum, Agilent Technologies, pp. 1-9, 2016 (Agilent) and Diamantis et al., British Journal of Cancer (2016) 114, 362–367 (hereinafter “Diamantis”).
Lannutti II teaches the recited conjugates:
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Lannutti II also teaches the instant ant-ROR1 antibody:
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wherein Heavy Chain SEQ ID NO: 3 and Light Chain SEQ ID NO: 4 correspond to the instant Heavy and Light Chains SEQ ID NOS: 1 and 2, respectively
Lannutti II may not explicitly teach the instant effective amounts and regimens. Nonetheless, the amount of the recited conjugate as an effective dose is a result-effective parameter that will affect the pharmacological and pharmacokinetic properties of the final composition. In this manner, the amount of a specific ingredient in a composition is clearly a result-effective parameter that a person of ordinary skill in the art would routinely optimize.
Specifically, it would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve a desired result. For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, usually rats, rabbits, dogs, or pigs. The animal model also can be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
Therapeutic efficacy and toxicity, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population), can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED5o. Pharmaceutical compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active ingredient or to maintain the desired effect. Factors which can be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions can be administered once or twice daily every 3 to 4 days, every week, or once every two weeks depending on the half-life and clearance rate of the particular formulation.
Normal dosage amounts can vary from micrograms to 100,000 micrograms, up to a maximum total dose, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
In this way, optimization of these parameters is a routine practice, and consequently, would be prima facie obvious, absent factual evidence demonstrating an unexpected benefit of the claimed amount(s).
Those of ordinary skill would have a reasonable expectation that the conjugate can treat the recited cancer since ROR1 is expressed on human malignancies.
Any observed pharmacological effects (see claim 15 and 16 i.e., eradication) would have been a necessary aspect of the conjugates, see MPEP 2112.01 (“Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”).
With regard to DAR, there are a limited and finite number of DAR’s for a given antibody- drug conjugate (ADC), around 8. Optimization of the DAR is a critical part of ADC development, since the DAR value affects the efficacy of the drug, as low drug loading reduces the potency, while high drug loading can negatively affect pharmacokinetics (PK)1 and toxicity. At the time the invention was made, easy, accurate and reproducible DAR calculation of ADC’s was within the purview of those of ordinary skill, see Agilent:
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In this manner, it would have been obvious to one have ordinary skill in the art at the time that applicant’s inventions was made to have made ADC’s with the recited DAR with a reasonable expectation that the resulting ADC with a DAR within the claimed range would be useful in treating cancer. In this connection, it is well-settled that ADC’s with a DAR from 1-8 are well within the purview of those of ordinary skill; and it would have been obvious to one of ordinary skill in the art at the time the invention was made to choose from this finite number of DAR options with a reasonable expectation of success of producing a ADC functional with a functional DAR.
Specifically, it is well within the skill of the artisan to try any of the 1-8 DAR’s. As outlined above, a DAR value affects the efficacy of the drug, as low drug loading reduces the potency, while high drug loading can negatively affect pharmacokinetics (PK)1 and toxicity. Here, a skilled chemist at the time would simply make the known ADC’s of the known 8 DAR’s. Indeed, it would have been part and parcel to make the different DAR’s to find one that is pharmaceutically acceptable.
With regard to any unpredictability associated with the DAR’s, the notion that unpredictability confers patentability in cases of DAR’s of known ADC’s should be disregarded since a rule of law equating unpredictability to patentability, applied in this case, would mean that any new ADC based on a different DAR would be separately patentable, simply because the formation and properties of each ADC must be verified through testing. This cannot be the proper standard since the expectation of success need only be reasonable, not absolute.
Here, the references provide the reasonable expectation of success, as outlined above. Namely, the references demonstrate the reasonable expectation of success since the references sufficiently characterize the instant ADC’s including the required heavy and light chains, i.e. (SEQ ID NO’s), conjugated to MMAE via a val/cit linker. Again, the expectation of success need only be reasonable, as it is here, and not absolute, (“obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).”).
Rather, Applicant has conducted a common optimization of the known DAR’s to produce the claimed ADC, which is routine. Specifically, Applicant engaged in routine, verification testing to optimize selection of one of several known and clearly suggested DAR’s to prepare a pharmaceutically-acceptable conjugate. In this regard, creating a “product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient . . . to enhance commercial opportunities . . . is universal—and even common-sensical.” see DyStar Textilfarben GmbH v. C.H. Patrick Co., 464 F.3d 1356 at 1368.
The rejected claims cover treatment DLBCL and MCL or not specifically taught by the references. However, antibody-drug conjugates (ADCs) offer benefits in cancer therapy beyond traditional chemo-, hormone- and immune checkpoint-therapies by selectively targeting cancer cells and delivering potent cytotoxic drugs directly to cancer cells, increasing effectiveness and reducing side effects compared to traditional chemotherapy. This targeted delivery improves the "therapeutic index" by increasing drug concentration in the tumor while decreasing it in healthy tissues, see Diamantis (“Antibody-drug conjugates (ADCs) are an emerging novel class of anticancer treatment agents that combines the selectivity of targeted treatment with the cytotoxic potency of chemotherapy drugs. New linker technology associated with novel highly potent cytotoxic payloads has permitted the development of more effective and safe ADCs. In recent years, two ADCs have been licensed, T-DM1 and brentuximab vedotin, and are already establishing their place in cancer treatment. A plethora of ADCs are being investigated in phases I and II trials, emerging data of which appears promising. As we deepen our understanding of what makes a successful ADC, an increasing number of ADCs will likely become viable treatment options as single agents or in combination with chemotherapy. This review will present the philosophy underlying ADCs, their main characteristics and current research developments with a focus on ADCs in solid tumours.”).
In this way, those of ordinary skill could have applied the instant ADC’s in the manner required and in a predictable fashion for the purposes of treating DLBCL and MCL. As discussed above, Diamantis is added for the proposition that ADC’s are applicable to treating the recited cancers. Specifically, Diamantis teaches the particular known technique of using ADC’s an alternate therapy for treating cancers was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to the recited cancers would have yielded predictable results. Accordingly, using the instant ADC’s to treat DLBCL and MCL would have been prima facie obvious.
Applicant has amended the claims to recite:
the cancer being treated is limited to previously treated DLBCL or MCL;
the dose administered is between 1.5 and 4.0 mg/kg;
the DAR of the Immunoconjugate (I) of claim 1 is between 3 and 5; and
(iv) the administration is limited to the 3 dosing schedules (a), (b), and (c).
Applicant argues that that the applied references, either individually or in combination, would have suggested or motivated a skilled artisan to adopt the method recited in the presently amended claims.
However, Diamantis demonstrates that ADC’s provide targeted delivery improves the "therapeutic index" by increasing drug concentration in the tumor while decreasing it in healthy tissues. The recited antibody-mc-vc-pab-mmae conjugates have shown to be effective in this regard. Therefore, the references provide a reasonable expectation that the recited ADC’s can treat DLBCL and MCL.
The recited DAR’s are within the optimization of those of ordinary skill, as discussed above.
Similarly, as outlined above, optimizing chemotherapy regimens and doses involves balancing maximum tumor destruction with minimal patient toxicity and is well within the purview of those of ordinary skill, in the absence of unexpected results.
The rejection under obvious double patenting is withdrawn in favor of the following new grounds of rejection under this section, which was necessitated by Applicant’s amendments.
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, 7-9, 12, 14, 15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8-12, 36-40, 43-47, 64-68 of U.S. Patent No. 10335496 in view of Agilent and Diamantis, cited above.
Although the claims at issue are not identical, they are not patentably distinct from each other. Specifically, the conflicting claims anticipate the rejected claims.
In particular, SEQ ID NOS; 5 and 6 correspond to VH and VL chains of the instant Heavy and Light chains of SEQ ID Nos: 1 and 2, respectively. The MC-Val-CIT -PAB-MMAE is also covered by the conflicting claims. In this regard, the difference between the conjugates covered in the rejected claims and those covered in the rejected claims is the conflicting claims may not recite the structure of the instant conjugates with particularity so as to amount to anticipation (See M.P.E.P. § 2131: "[t]he identical invention must be shown in as complete detail as is contained in the ... claim." Richardson v. Suzuki Motor Co., 868 F.2d 1226, 1236, 9 USPQ2d 1913, 1920 (Fed. Cir. 1989). The elements must be arranged as required by the claim, but this is not an ipsissimis verbis test, i.e., identity of terminology is not required. In re Bond, 910 F.2d 831, 15 USPQ2d 1566 (Fed. Cir. 1990).). However, the conflicting claims recite the structural elements of the claimed invention with sufficient guidance, particularity, and with a reasonable expectation of success, that the invention would be prima facie obvious to one of ordinary skill (the prior art reference teaches or suggests all the claim limitations with a reasonable expectation of success. See M.P.E.P. § 2143).
The conflicting claims may not explicitly teach the instant effective amounts and regimens. Nonetheless, the amount of the recited conjugate as an effective dose is a result-effective parameter that will affect the pharmacological and pharmacokinetic properties of the final composition. In this manner, the amount of a specific ingredient in a composition is clearly a result-effective parameter that a person of ordinary skill in the art would routinely optimize.
Specifically, it would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve a desired result. For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, usually rats, rabbits, dogs, or pigs. The animal model also can be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
Therapeutic efficacy and toxicity, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population), can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED5o. Pharmaceutical compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active ingredient or to maintain the desired effect. Factors which can be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions can be administered once or twice daily every 3 to 4 days, every week, or once every two weeks depending on the half-life and clearance rate of the particular formulation.
Normal dosage amounts can vary from micrograms to 100,000 micrograms, up to a maximum total dose, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
In this way, optimization of these parameters is a routine practice, and consequently, would be prima facie obvious, absent factual evidence demonstrating an unexpected benefit of the claimed amount(s).
Those of ordinary skill would have a reasonable expectation that the conjugate can treat the recited cancer since ROR1 is expressed on human malignancies.
Any observed pharmacological effects (see claim 15 and 16 i.e., eradication) would have been a necessary aspect of the conjugates, see MPEP 2112.01 (“Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”).
Applicant has not distinguished the claims of the conflicting patent, or any reissue thereof, from the rejected claims. Therefore, the rejection is maintained.
Specifically, Agilent and Diamantis teach or suggest the amended subject matter, as outlined above.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARL J PUTTLITZ whose telephone number is (571)272-0645. The examiner can normally be reached on Monday to Friday from 9 a.m. to 5 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Gregory Emch, can be reached at telephone number 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARL J PUTTLITZ/ Primary Examiner, Art Unit 1646
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