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
Status of Application/Election/Restrictions
Claims 1-19 are pending in this application and under examination in this office action.
Specification
The disclosure is objected to because of the following informalities: The use of the term “CellSave” (p. 15, para.[0066]; [0070]), “CellSieveTM” (p.15, para. [0069]-[0070]; p. 16, [0071]), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Appropriate correction is required.
Claim Objections
Claims 1-4 and 9 are objected to because of the following informalities: The recitation “CAMLs” recited in claims 1-4 and the recitation “EpCAM” recited in claim 9 are not unique or common abbreviations in the art. Applicants are required to spell out “CAMLs” and “EpCAM” at the first usage. Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claims 1-19 are indefinite because:
i. Claims 1-4 recite the limitation "the size of CAMLs" in line 2 of the claim. There is insufficient antecedent basis for this limitation in the claim.
ii. Regarding claims 1-2, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
iii. Regarding claim 2, the term “atypical” or the term “two legs, more than two legs, thin legs and amorphous” in claim 2 is a relative term which renders the claim indefinite. The term “atypical” or the term “two legs, more than two legs, thin legs and amorphous” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Applicant fails to set forth the metes and bounds of what is encompassed within the definition of “atypical” or “two legs, more than two legs, thin legs and amorphous”. Since the metes and bounds are unknown, a skilled artisan cannot envision what would be considered as ““atypical” or “two legs, more than two legs, thin legs and amorphous” recited in the claim. Thus the claim is indefinite.
iv. Claim 10 recites the limitation "the source " in line 1 of the claim. There is insufficient antecedent basis for this limitation in the claim.
v. Regarding claim 13, Claim limitation “one or more means… or a combination thereof” invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. There is no clear linkage between the structure, material, or acts for the recited size exclusion methodology, immunocapture, red blood cell lysis, white blood cell depletion, FICOLL, electrophoresis, dielectrophoresis, flow cytometry, magnetic levitation and various microfluidic chips or a combination thereof, and the function of isolating CAMLs. The structure, CellSieveTM or a Creatv MicroTech CellSieveTM low-microfiltration assay alone or H&E stains alone described in the specification without specific antibodies for characteristics and markers recited in claims 8-9 does not perform the entire function in the claim, such as isolating CAMLs with a size of about 100mm or more or having characteristics recited in claims 8-9. Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
vi. Regarding claim 13, the term “various microfluidic chips” in claim 13 is a relative term which renders the claim indefinite. The term “various microfluidic chips” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Applicant fails to set forth the metes and bounds of what is encompassed within the definition of “various microfluidic chips””. Since the metes and bounds are unknown, a skilled artisan cannot envision what would be considered as “various microfluidic chips” recited in the claim. Thus the claim is indefinite.
vii. Regarding claim 13, claim 13 contains the trademark/trade name “FICOLL”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112, second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a density gradient medium for separating cells and, accordingly, the identification/description is indefinite
viii. Regarding claim 17, the term “precision pore geometry and uniform pore distribution” in claim 17 is a relative term which renders the claim indefinite. The term “precision pore geometry and uniform pore distribution” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Applicant fails to set forth the metes and bounds of what is encompassed within the definition of “precision pore geometry and uniform pore distribution”. Since the metes and bounds are unknown, a skilled artisan cannot envision what would be considered as “precision pore geometry and uniform pore distribution” recited in the claim. Thus, the claim is indefinite.
ix. Regarding claim 18, the term “large cell” or “small cells” in claim 18 is a relative term which renders the claim indefinite. The term “large cell” or “small cells” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Applicant fails to set forth the metes and bounds of what is encompassed within the definition of “large cell” or “small cells”. Since the metes and bounds are unknown, a skilled artisan cannot envision what would be considered as “concentrating large cell” or “eliminating small cells” recited in the claim. Thus the claim is indefinite.
x. Regarding claim 19, the term “low-pressure” in claim 19 is a relative term which renders the claim indefinite. The term “low-pressure” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Applicant fails to set forth the metes and bounds of what is encompassed within the definition of “low-pressure”. Since the metes and bounds are unknown, a skilled artisan cannot envision what would be considered as “low-pressure microfiltration assay” recited in the claim. Thus, the claim is indefinite.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claim(s) recite(s) diagnosing or predicting development of multiple organ metastasis and/or multifocal metastatic disease based on a correlation between the presence of at least one CAML with a size of about 100mm or more in a biological sample from a subject and the presence of multiple organ metastasis and/or multifocal metastatic disease in the subject or predicting overall survival (OS) and/or progression of free survival of a subject having cancer based on a correlation between the presence of at least one CAML with size of about 100mm or more in a biological sample from the subject compared to a subject having the same or similar cancer but lacking at least one CAML1 with size of about 100mm or more in a corresponding sample. This correlation is a consequence of natural phenomenon in the biological sample of patients having cancer with multiple organ metastasis and/or multifocal metastatic disease, which is a judicial exception.
The claims are directed to a law of nature or a natural phenomenon judicial exception because the claims recite diagnosing multiple organ metastasis and/or multifocal metastatic disease and determining the size of CAMLs in patients suffering from cancer based on a correlation between the presence of at least one CAML in size of about 100mm or more in the biological sample of the cancer patient and the presence of multiorgan metastasis and/or multifocal metastatic disease in patients suffering from cancer. In addition, the limitations “determining the size of CAMLs…wherein when at least one CAML is said sample is about 100mm or more in size, the subject is diagnosed to have multiple organ metastases and/or multifocal metastatic disease” in claim 1, “determining the size of CAMLs in a biological sample….the subject is predicted to develop multiple organ metastases and/or multifocal metastatic disease” in claim 2, “determining the size of CAMLs…the subject ins predicted to have shorter OS and/or shorter PFS than a subject having the same…..in size” in claim 3, and “determining the size of CAMLs…the OS/and/or PFS of the subject is predicted to be less or shorter than a subject having cancer wherein none of the CAMLs is more than about 100mm in size” in claim 4 are a mental step-type abstract idea and thus is a judicial exception. The presence of at least one CAML in size of about 100mm or more in the biological sample of patients having cancer compared to cancer patients with no CAML in size of about 100mm or more is a law of nature or a natural phenomenon, which is a judicial exception. This correlation is a consequence of natural phenomenon, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo, and thus the claims are directed to a judicial exception (Step 2A Prong 1: Yes).
This judicial exception is not integrated into a practical application because the invention provides no improvement to any other technology or technical field (see MPEP 2106.05(a)) or transform into a different technology (see MPEP 2106.05(b)-(c)), does not apply or use a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition (see Vanda Memo), and does not apply or use the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception (see MPEP 2106.05(e) and Vanda Memo).
The invention provides no improvement to any other technology or technical field (see MPEP §2106.05(a)) because the claims themselves do not have any limitations that address this issue. The invention does not use a judicial exception in conjunction with, a particular machine or to transform a particular technology to a different technology (See MPEP §2106.05 (b)-(c)). The different characteristics of CAMLs recited in claim 8-9 are well-known characteristics for CAMLs as evidenced by Adams et al. (see para. [0014]-[0016]; [0051]-[0056]; [0077]-[0078] in WO2018/151865, as in IDS). The different methods recited in claim 13 to isolate CAMLs are also well-known techniques as evidenced by Adams et al. (see para. [0019]-[0021]; [0082]-[0087] in WO2018/151865). Thus, the isolating/detecting step does not integrate the mental step of determining or the judicial exception into a practical application because the claims provide no improvement in technology or transform the detecting or isolating CAMLs to a different technology. The invention does not apply or use a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition (see Vanda Memo) because the claims themselves do not have any limitations that address these issues.
The invention also does not apply or use the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception (see MPEP 2106.05(e) and Vanda Memo). The claims recite a natural correlation between the presence of at least one CAML with a size of about 100mm or more in the biological sample of the patient with cancer and the presence of multiple organ metastasis and/or multifocal metastatic disease in the patient with cancer, or a natural correlation between the presence of at least one CAML with a size of about 100mm or more in the biological sample of the patient with cancer and a shorter OS and/or PFS in the patients with cancer compared to the patient with cancer and without CAML with a size of about 100mm or more (law of nature). The additional elements/steps of "determining the size of CAMLs …” in claims 1-4, “said OS and/or PFS is over a period of at least 12 months/24 months” in claims 5-6, “the size of the biological sample is between 5 and 15 ml” in claim 7, “wherein the CAMLs have the following characteristics…..” in claims 8-9, “the source of the biological sample is….urine” “antecubital-vein blood….” In claims 10-11, different cancers in claim 12 are insignificant extra-solution activities and mere data gathering as determined by the court. See Mayo, 566 U.S. at 79, 101 USPQ2d at 1968 and PerkinElmer, Inc. v. Intema Ltd., 496 Fed. App'x 65, 73, 105 USPQ2d 1960, 1966 (Fed. Cir. 2012) and MPEP §2106.05(g). The limitations “wherein CAMLs are isolated…the group consisting of size exclusion methodology, …and various microfluidic chips or a combination thereof” in claim 13, “using size exclusion methodology that comprises using a microfilter” in claim 14, “wherein the microfilter has a pore size ranging from about 5 micron to about 20 micron” in claim 15 , “the pores of the microfilter have a round, race-track….pore shape” in claim 16, “wherein the microfilter has precision pore geometry…distribution” in claim 17, “using a microfluidic chip via physical size-based sorting….based on size” in claim 18 or “using a low-pressure microfiltration assay” in claim 19 only generally links the use of the judicial exception (diagnose multiple organ metastasis and/or multifocal metastatic disease based on a correlation between the presence of at least one CAML in size of about 100mm or more in the biological sample of the cancer patient and the presence of multiorgan metastasis and/or multifocal metastatic disease in patients suffering from cancer) are merely extra-solution activities or a field of use as evidenced by Adams et al. (see p. 3518, Adams et al., PNAS, 2014; 111:3514-3519), Tang et al. (see p. 1247; Tang et al., Cytometry Part A, 2018; 93A:1246-1250), Adams et al. (see p. 1038, Adams et al., Cancer Epidemiol. Biomarkers Prev.; 2016; 25:1037-42) or Mu et al. (see p. 734, 2nd col. to p. 735, 1st col.; Mu et al., Breast Cancer Res. Treat., 2017; 165:733-741), or Adams et al. (para. [0014]-[0016]; [0051]-[0056]; [0077]-[0078]; para. [0019]-[0021]; [0082]-[0087] in WO2018/151865, as in IDS), and thus only provides a nominal or insignificant relationship to the exception(s) and is merely extra-solution activity or a field of use. See MPEP 2106.05(g)-(h). Thus, the additional element or the isolating/detecting step does not integrate the judicial exception into a practical application (Step 2A Prong 2: No).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite elements/steps in addition to the judicial exception(s) that are well-understood, purely conventional or routine in the relevant field, the elements/steps recited in the claims in addition to the judicial exception(s) that are insignificant extra-solution activity, e.g., are merely appended to the judicial exception(s) and amount to nothing more than a mere field of use in view of MPEP 2106.05(d)-(h) and Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017).
The limitations “determining the size of CAMLs…wherein when at least one CAML is said sample is about 100mm or more in size, the subject is diagnosed to have multiple organ metastases and/or multifocal metastatic disease” in claim 1, “determining the size of CAMLs in a biological sample….the subject is predicted to develop multiple organ metastases and/or multifocal metastatic disease” in claim 2, “determining the size of CAMLs…the subject ins predicted to have shorter OS and/or shorter PFS than a subject having the same…..in size” in claim 3, and “determining the size of CAMLs…the OS/and/or PFS of the subject is predicted to be less or shorter than a subject having cancer wherein none of the CAMLs is more than about 100mm in size” in claim 4 are mental steps, which is a judicial exception.
The limitations “wherein CAMLs are isolated…the group consisting of size exclusion methodology, …and various microfluidic chips or a combination thereof” in claim 13, “using size exclusion methodology that comprises using a microfilter” in claim 14, “wherein the microfilter has a pore size ranging from about 5 micron to about 20 micron” in claim 15 , “the pores of the microfilter have a round, race-track….pore shape” in claim 16, “wherein the microfilter has precision pore geometry…distribution” in claim 17, “using a microfluidic chip via physical size-based sorting….based on size” in claim 18 or “using a low-pressure microfiltration assay” in claim 19 are merely extra-solution activity or a field of use as evidenced by Adams et al. (see p. 3518, Adams et al., PNAS, 2014; 111:3514-3519), Augustyn et al. (see p. e452, Augustyn et al., Clinical Lung Cancer, 2020; 22:e451-65), Tang et al. (see p. 1247; Tang et al., Cytometry Part A, 2018; 93A:1246-1250), Adams et al. (see p. 1038, Adams et al., Cancer Epidemiol. Biomarkers Prev.; 2016; 25:1037-42), Mu et al. (see p. 734, 2nd col. to p. 735, 1st col.; Mu et al., Breast Cancer Res. Treat., 2017; 165:733-741), or Adams et al. (para. [0014]-[0016]; [0051]-[0056]; [0077]-[0078] in WO2018/151865, as in IDS), and thus only provides a nominal or insignificant relationship to the exception(s) and is merely extra-solution activity or a field of use. See MPEP 2106.05(g)-(h). Thus, the additional elements/steps recited in the claims are a well-understood, purely conventional or routine in the art or relevant field to isolate CAMLs and determine the size of CAMLs in a blood sample obtained from a patient with cancer. These additional elements/steps do not amount to significantly more than the exception itself because the additional elements/steps only apply conventional techniques (i.e. using CellSearch CTC kits or CellSieve microfiltration assays and immunostaining with DAPI and an antibody cocktail against cytokeratins 8, 18, 19, EpCAM and CD45) to detect the natural law (i.e. the presence of at least one CAML with a size of about 100mm or more in the biological sample of the patient with cancer compared to patients with cancer and no CAML with a size of about 100mm or more). The combination of judicial exception with additional elements is insufficient to ensure that the claims amount to significantly more than the exception itself because these additional elements/steps are mere field of use that impose no meaningful limit on the performance of the method and are no more than well-understood, purely conventional, and routinely taken by others in order to apply the natural principle (Step2B: No). Accordingly, claims 1-19 are not patent eligible because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-19 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
Claims 1-19 encompass determining the size of a genus of CAMLs isolated from the subject with cancer.
Claims 13-19 encompass using a genus of one or more means selected from the group consisting of size exclusion methodology, immunocapture, red blood cell lysis, white blood cell depletion, FICOLL, electrophoresis, dielectrophoresis, flow cytometry, magnetic levitation and various microfluidic chips or a combination thereof for isolating CAMLs.
Applicant has not disclosed sufficient species for the broad genus of CAMLs isolated from the subject with cancer or the broad genus of one or more means recited in claims 13-19 for isolating CAMLs or hyper-engorged CAMLs larger than 100mm (heCAMLs) expressing markers including CD14, CD45, EpCAM, vimentin, PD-L1, CD11c, CD146, CD202b and CD31 recited in claims 8-9 or in figure 1 (see para. [0042]-[0045], figure 1).
The specification only describes using CellSieveTM microfilters with H &E stains or a Creatv MicroTech CellSieveTM low-microfiltration assay with a specific cocktail of antibodies for characteristics and markers recited in claims 8-9, and passing a 15ml sample (which contains 7.5ml of whole blood prefixed with 7.5ml of prefixation buffer) through the CellSieveTM microfilter in 3min, and using a fluorescence antibody mixture staining the cells captured on the filter, and imaging and measuring on a fluorescent microscope using ZenBlue, wherein the CellSieveTM microfileter is a size-exclusion device with 7.5mm-diameter pores, 180,000 pores distributed uniformly within a 9mm-diameter area on a strong, low-autofluorescence, 10 mm-thick polymer and the filtration is performed under low pressure using a syringe pump or a vacuum pump (see para. [0069]-[0070]) to isolate CAMLs with characteristics recited in claims 8-9, and wherein the fluorescent antibody mixture includes antibodies against CD14, CD45, EpCAM, vimentin, PD-L1, CD11c, CD146, CD202b and CD31 recited in claims 8-9 or in figure 1 (see para. [0042]-[0045], figure 1).
However, the claims are not limited to the CAMLs isolated using the agents, steps and methods set forth above.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is in possession of and what Applicant is claiming.
M.P.E.P. § 2163 instructs:
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. . . .
An applicant may show possession of an invention by disclosure of drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole. . . .
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.”
This standard has not been met in this case. From the specification and the prior art, Applicant is in possession of isolating CAMLs or hyper-engorged CAMLs larger than 100mm (heCAMLs) expressing markers including CD14, CD45, EpCAM, vimentin, PD-L1, CD11c, CD146, CD202b and CD31 recited in claims 8-9 or in figure 1 (see para. [0042]-[0045], figure 1) using a Creatv MicroTech CellSieveTM low-microfiltration assay with a specific cocktail of antibodies against markers recited in claims 8-9 and passing 15ml sample (7.5ml of whole blood prefixed with 7.5ml of prefixation buffer) through the CellSieveTm microfilter in 3min, and fluorescence antibody mixture staining the cells captured on the filter and imaging and measuring on a fluorescent microscope using ZenBlue, wherein the CellSieveTM microfileter is a size-exclusion device with 7.5mm-diameter pores, 180,000 pores distributed uniformly within a 9mm-diameter area on a strong, low-autofluorescence, 10 mm-thick polymer and the filtration is performed under low pressure using a syringe pump or a vacuum pump (see para. [0069]-[0070]), and wherein the fluorescent antibody mixture includes antibodies against CD14, CD45, EpCAM, vimentin, PD-L1, CD11c, CD146, CD202b and CD31 recited in claims 8-9 or in figure 1 (see para. [0042]-[0045], figure 1).
However, Applicant is not in possession of other structurally and functionally undefined CAMLs or using other structurally and functionally undefined means selected from the group consisting of size exclusion methodology, immunocapture, red blood cell lysis, white blood cell depletion, FICOLL, electrophoresis, dielectrophoresis, flow cytometry, magnetic levitation and various microfluidic chips or a combination thereof for isolating CAMLs or HeCAMLs expressing characteristics and markers recited in claims 8-9.
The specification provides no identification of any particular structure that must be conserved for the claimed genus of CAMLs or HeCAMLs expressing characteristics and markers recited in claims 8-9 or the claimed genus of one or more means recited in claims 13-19 for isolating CAMLs or HeCAMLs expressing characteristics and markers recited in claims 8-9. The instant specification fails to provide sufficient descriptive information, such as definitive structural or functional features of the claimed genus of CAMLs or HeCAMLs expressing characteristics and markers recited in claims 8-9 or the claimed genus of one or more means recited in claims 13-19 for isolating CAMLs or HeCAMLs expressing characteristics and markers recited in claims 8-9. There is no description of the conserved structures which are critical to the function of the claimed genus. There is no information regarding the relation of structure of the claimed genus of other CAMLs to the function of CAMLs or HeCAMLs expressing characteristics and markers recited in claims 8-9. There is no information regarding the relation of structure of the claimed genus of other structurally and functionally undefined means recited in claims 13-19 to the function of using a Creatv MicroTech CellSieveTM low-microfiltration assay with a specific cocktail of antibodies against markers recited in claims 8-9. Furthermore, the prior art does not provide compensatory structural or correlative teachings sufficient to enable one of skill to isolate and identify what other CAMLs might be, and what other means recited in claims 13-19 for isolating CAMLs or HeCAMLs expressing characteristics and markers recited in claims 8-9 might be. Since the common characteristics/features of other CAMLs or other means recited in claims 13-19 for isolating CAMLs or HeCAMLs expressing characteristics and markers recited in claims 8-9 are unknown, a skilled artisan cannot envision the functional correlations of the genus with the claimed invention. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the genus of CAMLs or the genus of means recited in claims 13-19 for isolating CAMLs or HeCAMLs expressing characteristics and markers recited in claims 8-9.
Based on MPEP § 2161.01 and §2163, “to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116”.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of CAMLs or means recited in claims 13-19 for isolating CAMLs or HeCAMLs expressing characteristics and markers recited in claims 8-9, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483.
Therefore, the claimed methods have not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
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 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.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gironda et al. (J. Clin. Oncol. May 28, 2021; 39: 3039 (Meeting Abstract:2021 ASCO Annual Meeting) as evidenced by Adams et al. (WO2018/151865).
Claims 1-19 are drawn to methods for diagnosing multiple organ metastasis and/or multifocal metastatic disease in a subject, predicting development of multiple organ metastasis and/or multifocal metastatic disease in a subject and predicting overall survival (OS) and/or progression free survival (PFS) of a subject having cancer, the method comprising determining the size of CAMLs in a biological sample from a subject having cancer, wherein when at least one CAML in the sample is about 100 mm or more in size, the subject is diagnosed to have multiple organ metastases and/or multifocal metastatic disease or the subject is predicted to develop multiple organ metastases and/or multifocal metastatic disease, or the subject is predicted to have shorter OS and/or shorter PFS than a subject having the same or similar cancer but lacking at least one CAML in a corresponding sample about 100mm or more in size.
Gironda et al. teaches methods for diagnosing multiple organ metastasis and/or multifocal metastatic disease in a subject, predicting development of multiple organ metastasis and/or multifocal metastatic disease in a subject, predicting overall survival (OS) and/or progression free survival (PFS) of a subject having cancer and predicting OS and/or PFS of a subject having cancer, comprising determining the size of CAMLs in a biological sample from a subject having metastatic breast (mbreast), lung (mlung), prostate (mprostate) and renal (mrenal) cancers, and wherein the patients with mbreast, mlung, mprostate or mrenal have at least one CAML with size of ≥ 100 mm (heCAMLs) as in claims 1-4 (see p 1-2, abstract). Gironda teaches that the presence of heCAMLs is an indicator of multiorgan metastasis and/or multifocal metastatic disease, and the presence of heCAML predicted that the patient with mbreast, mlung, mprostate or mrenal with a shorter OS/PFS than those without heCAMLs over a period of 24 months (which is at least 12 month or 24 moths as in claims 5-6 (see p.1-2, abstract).
Gironda teaches that the heCAMLs are isolated from peripheral blood from patients with metastatic cancer using standard CellSieveTM techniques, then imaged and measured in ZenBlue, which include size exclusion methodology, immunocapture, red blood cell lysis, white blood cell depletion, FICOLL, electrophoresis, dielectrophoresis, flow cytometry, magnetic levitation, and various microfluidic chips, or a combination thereof, and that the size exclusion methodology comprises using a microfilter, wherein the microfilter has a pore size ranging from about 5 microns to about 20 microns and has precision pore geometry and uniform pore distribution; and wherein the pores of the microfilter have a round, race-track shape, oval, square and rectangular pore shape recited in claims 7, 10-11 and 13-19 as evidenced by Adams et al. (WO2018/151865, as in IDS; see para. [0019]-[0021]; [0082]-[0087]). The cancer disclosed by Gironda includes stages 1-4, metastatic breast cancer, prostate cancer, lung cancer and renal cancer in claim 12 (see p.1-2, abstract). The heCAMLs disclosed by Giornda have the characteristics including “large atypical polyploid nucleus of about 14-64 mm in size…cell size of about 20-300mm in size, and morphological shape…and amorphous” recited in claim 8 and “CD14 positive….CD31 marker expression” recited in claim 9 as evidenced by Adams et al. (WO2018/151865) (see para. [0014]-[0016]; [0051]-[0056]; [0077]-[0078]). Thus, claims 1-19 are anticipated by Gironda et al. as evidenced by Adams et al..
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 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over Adams et al. (WO2018/151865, published Aug 23, 2018, priority Feb 16, 2017, as in IDS; also published as US2020/0003781, as in IDS).
Adams et al. (WO2018/151865) teach that methods for predicting overall survival (OS) and/or progression free survival (PFS) of a subject having cancer, the method comprising determining the size of CAMLs in a biological sample from a subject having cancer, wherein when at least one CAML in the sample is about 50 mm or more in size, the subject is predicted to have shorter OS and/or shorter PFS than a subject having the same or similar cancer but lacking at least one CAML in a corresponding sample about 50mm or more in size (see [0008]-[0009]; p. 16-20, Examples). Adams taches that the OS and/or PFS of the subject with larger-sized CAMLs is predicted to be less than the OS and PFS of the subject having smaller-sized cells (see [0008]-[0009]). Adams teach that the OS and/or PFS is over a period of at least 12 months or at least 24 months as in claims 5-6 (see [0012]; [0072]). Adams teach that the size of the biological sample is 5-15ml as in claim 7 (see [0013]; [0075]-[0076]). Adams teaches that the CAMLs having the characteristics: (a) large atypical polyploid nucleus of about 14-64 pm in size, or multiple nuclei in a single cell; (b) cell size of about 20-300 pm in size; and (c) morphological shape selected from the group consisting of spindle, tadpole, round, oblong, two legs, more than two legs, thin legs, and amorphous recited in claim 8 or with additional characteristics: (d) CD14 positive phenotype; (e) CD45 expression; (f) EpCAM expression; (g) vimentin expression; (h) PD-L1 expression; (i) monocytic CD 11C marker expression; (j) endothelial CD146 marker expression; (k) endothelial CD202b marker expression; and (1) endothelial CD31 marker expression recited in claim 9 (see [0014]-[0016]; [0051]-[0056]; [0077]-[0078]). Adams teaches the source of the biological sample is one or more of peripheral blood, blood, lymph node, bone marrow, cerebral spinal fluid, tissue, and urine or antecubital-vein blood, inferior-vena-cava blood, femoral vein blood, portal vein blood, or jugular-vein blood as in claims 10-11 (see [0017]; [0079]).
Adams teaches that the cancer is a solid tumor, Stage I cancer, Stage II cancer, Stage III cancer, Stage IV cancer, carcinoma, sarcoma, neuroblastoma, melanoma, epithelial cell cancer, breast cancer, prostate cancer, lung cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, head and neck cancer, kidney cancer, ovarian cancer, esophageal cancer or other solid tumor cancer in claim 12 (see [0018]; [0081]). Adams teaches that the CAMLs are isolated from the biological samples for the determining steps using one or more means selected from the group consisting of size exclusion methodology, immunocapture, red blood cell lysis, white blood cell depletion, FICOLL®, electrophoresis, dielectrophoresis, flow cytometry, magnetic levitation, and various microfluidic chips, or a combination thereof, and that the size exclusion methodology comprises using a microfilter, wherein the microfilter has a pore size ranging from about 5 microns to about 20 microns and has precision pore geometry and uniform pore distribution; and wherein the pores of the microfilter have a round, race-track shape, oval, square and rectangular pore shape as in claim 12 ([0019]-[0020]; [0082]-[0087]). Adams teaches that the CAMLs are isolated using a microfluidic chip via physical size-based sorting, hydrodynamic size-based sorting, grouping, trapping, immunocapture, concentrating large cells, or eliminating small cells based on size as in claim 18 or a CellSieveTM low-pressure microfiltration assay as in claim 19 (see [0021]-[0022]).
But Adams does not explicitly teach using the size of about 100mm as a cutoff value for CAMLs as an indicator. However, Adams teaches that the size of CAMLs at stages I-II is below 100mm (Figure 3A-B), and the number of CAML with size of ≥ 100mm in patients with stage 4 cancer (i.e. which is metastasized to multiple organs) is “1” (Figures 3A-3B). The OS/PFS of Stage IV based on CAML size of ≥ 100mm is shorter than the OS/PFS of stage I or II which has no CAML in size of ≥ 100mm over a period of at least 12 months or 24 months (Figures 9-11). Based on the teachings of Adams, it is apparent that the size of CAMLs in cancer patients with stage 4 metastasis to different organs is ≥ 100mm and the number of CAMLs in size of ≥ 100mm in cancer patients with stage 4 metastasis to different organs is at least one as compared to stage 1, 2 or 3 which lacks CAMLs in size of ≥ 100mm.
A person of ordinary skill in the art would have recognized that selecting applying the finding of the presence of CAMLs in size of ≥ 100mm in cancer patients with stage 4 metastasis to different organs compared to the absence of CAMLs in size of ≥ 100mm in patients with stages 1-3 and the known CAML size of ≥ 100mm in cancer patients with stage 4 metastasis to different organs and the known technique disclosed by Adams to the Adams’ method would have yielded the predictable result of diagnosing multiple organ metastasis and/or multifocal metastatic disease in a subject, predicting development of multiple organ metastasis and/or multifocal metastatic disease in a subject, predicting OS and/or PFS of a subject having cancer based on determining the size of CAMLs in a biological sample from a subject having cancer, wherein when at least one CAML in the sample is about 100 mm or more in size, the subject is diagnosed to have multiple organ metastases and/or multifocal metastatic disease or the subject is predicted to develop multiple organ metastases and/or multifocal metastatic disease, or the subject is predicted to have shorter OS and/or shorter PFS than a subject having the same or similar cancer but lacking at least one CAML in a corresponding sample about 100mm or more in size, and resulted in an improved method.
Including and using the size of ≥ 100mm as a cut-off value for CAMLs and the finding of the presence of at least one CAMLs in size of ≥ 100mm in cancer patients with stage 4 metastasis to different organs as an indicator in the Adams’ method would diagnose multiple organ metastases and/or multifocal metastatic disease in cancer patients, predict development of multiple organ metastases and/or multifocal metastatic disease in cancer patients, or predict a shorter OS and/or shorter PFS in the cancer patient than a subject having the same or similar cancer with no CAML in size of ≥ 100mm and would expand application of the Adams’ method and increase patient’s satisfaction with diagnosis or potential treatment of cancer because the CAMLs in size of ≥ 100mm can be found in cancer patients with stage 4 metastasis to different organs but not in stages I-III, and the number of CAMLs in size of ≥ 100mm in cancer patients with stage 4 metastasis to different organs is at least one as compared to cancer patients stage 1, 2 or 3 which lack CAMLs in size of ≥ 100mm.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known finding of the presence of CAMLs in size of ≥ 100mm in cancer patients with stage 4 metastasis to different organs compared to the absence of CAMLs in size of ≥ 100mm in patients with stages 1-3, the known CAML size of ≥ 100mm in cancer patients with stage 4 metastasis to different organs and the known technique disclosed by Adams to the Adams’ method, and yield the predictable result of diagnosing multiple organ metastasis and/or multifocal metastatic disease in a subject, predicting development of multiple organ metastasis and/or multifocal metastatic disease in a subject and predicting overall survival (OS) and/or progression free survival (PFS) of a subject having cancer based on determining the size of CAMLs in a biological sample from a subject having cancer and the presence of at least one CAML in size of ≥ 100mm in the biological sample compared to a subject having the same or similar cancer but lacking at least one CAML in a corresponding sample about 100mm or more in size.
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 1-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12516379, claims o1-13 and 20-26 U.S. Patent No.11156596, claims 1 and 4-15 of U.S. Patent No. 10871491, or claims 1-7 of U.S. Patent No.10247725 in view of Adams et al. (WO2018/151865).
Claims 1-14 of US12516379 (the ‘379 patent) claim methods of determining cancer progression in a subject, comprising isolating giant cells and optionally giant cell naked nuclei from a biological sample of a subject having cancer, and determining the size of giant cells and the number of cancer-associated mutations in the giant cells and/or giant cell naked nuclei, and determining cancer is progressing in the subject based on changes in the size and the number determined in (b), wherein when the size of the giant cells increase and the number of the cancer-associated mutations increase compared to those from a sample obtained from the subject at an earlier time point, cancer is determined to be progressing in the subject, and wherein the giant cells and giant cell nucleic are isolated using size exclusion methodology using a filter having a pore size that retains giant cells and giant cell naked nuclei of 8 micron and greater than 8 micron, and wherein the giant cells are polynucleated ranging in size of 25-300mm.
Claims 1-13 and 20-26 of US11156596 (the ‘596 patent) claim methods of screening a subject for cancer, confirming diagnosis of cancer in a subject, comprising detecting CAMLs in a biological sample from a subject previously determined to be high risk for cancer, wherein the detecting comprises (a) isolating intact cells of 20-300 microns in size from a biological sample obtained from a subject using a means selected from the group consisting of size exclusion methodology, immunocapture, red blood cell lysis, white blood cell depletion, microfiltration assay comprising high molecular weight polysaccharide separation, electrophoresis, dielectrophoresis, flow, cytometry, magnetic levitation, microfluidic chip and a combination thereof, and (b) selecting multi-nucleated cells isolated in (a) expressing CD31 and one or more markers of the following additional markers: cytokeratin (CK) 8, CK18, CK19, epithelial cell adhesion molecule (EpCAM), cluster of differentiation (CD) 45, vimentin, CD146, CD202b, CD11c or CD14, wherein antibodies are used to select cells expressing the one or more markers thereby detecting CAMLs in the biological sample from a subject, and wherein when CAMLs are detected in the biological sample, the subject is determined to have cancer.
Claims 1 and 4-15 of US10871491 (the ‘491 patent) claim a method for confirming diagnosis of cancer in a subject diagnosed with cancer, comprising detecting CAMLs in a biological sample from a subject previously determined to be high risk for cancer, wherein the detecting comprises (a) isolating intact cells of 20-300 microns in size from a biological sample obtained from a subject using a microfilter having pores of about 7-8 microns in size, wherein the biological sample is one or more of peripheral blood, blood, lymph node, bone marrow, CSF, tissue or urine, and (b) selecting cells isolated in (a) having the following characteristics: (i) multiple individual nuclei and/or large fused nucleoli having a size of about 14-64 pm diameter; (ii) morphological shape selected from the group consisting of spindle, tadpole, round, oblong and amorphous; and (iii) expressing one or more of the following markers: cytokeratin (CK) 8, CK18, CK19, vimentin, cluster of differentiation (CD) 45, CD11c, CD14, CD146, CD202b, or CD31, wherein antibodies are used to select cells expressing the one or more markers thereby detecting CAMLs in the biological sample from a subject, and wherein when CAMLs are detected in the biological sample, the subject is determined to have cancer.
Claims 1-7 of US10247725 (the ‘725 patent) claim methods of screening a subject for cancer, confirming diagnosis of cancer in a subject, comprising detecting CAML in a biological sample from a subject previously determined to be high risk for cancer, wherein the detecting comprises (a) isolating intact cells of 20-300 microns in size from a biological sample obtained from a subject using a microfilter having pores of about 7-8 microns, wherein the biological sample is peripheral blood, and (b) selecting multi-nucleated cells isolated in (a) expressing one or more markers: endothelial cell markers: CD146, CD202b and CD31, and monocyte markers: CD11c and CD14,wherein antibodies are used to select cells expressing the one or more markers thereby detecting CAMLs in the biological sample from a subject, and wherein when CAMLs are detected in the biological sample, the subject is determined to have cancer.
While the claims of the ‘379 patent, the ‘596 patent, the ‘491 patent or the ‘725 patent do not explicitly recite CAMLs in size of ≥ 100mm as indicator of diagnosis of multi organ metastasis and/or multifocal metastatic disease or predicting development of multi-organ metastasis and/or multifocal metastatic disease or OS/PFS in the subject with cancer, Adams et al. (WO2018/151865) teach these limitations and provide motivation and an expectation of success for the reasons set forth above under the 103 rejection.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known finding of the presence of CAMLs in size of ≥ 100mm in cancer patients with stage 4 metastasis to different organs compared to the absence of CAMLs in size of ≥ 100mm in patients with stages 1-3, the known CAML size of ≥ 100mm in cancer patients with stage 4 metastasis to different organs and the known technique disclosed by Adams to the methods of the ‘379 patent, the ‘596 patent, the ‘491 patent or the ‘725 patent; and yield the predictable result of diagnosing multiple organ metastasis and/or multifocal metastatic disease in a subject, predicting development of multiple organ metastasis and/or multifocal metastatic disease in a subject and predicting overall survival (OS) and/or progression free survival (PFS) of a subject having cancer based on determining the size of CAMLs in a biological sample from a subject having cancer and the presence of at least one CAML in size of ≥ 100mm in the biological sample compared to a subject having the same or similar cancer but lacking at least one CAML in a corresponding sample about 100mm or more in size.
Double Patenting
Claims 1-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-4, 6-9, 11, 16-17 and 19 of copending Application No. 16/486303, claims 1-3, 10-12, 15, 20 of copending Application No. 16/979742, or claims 1-2, 4-13 and 20-26 of copending Application No. 17509661 in view of Adams et al. (WO2018/151865).
Claims 2-4, 6-9, 11, 16-17 and 19 of Application No. 16/486303 (the ‘303 Application) claim methods for predicting overall survival (OS) and progression free survival (PFS) of a subject having cancer, comprising obtaining a blood sample from a subject having cancer and determining the size of circulating cells in the blood sample, wherein when at least one cell in the blood sample is about 50um or more in size, the OS and PFS of the subject is predicted to be less than a subject having cancer where none of the cells is more than 50um in size, determining a ratio of circulating cells in a selected volume of the blood sample, wherein the ratio is equivalent to about 6 or more cells per 7.5ml of the blood sample, the OS and PFS of the subject is predicted to be less than a subject having cancer with a ratio equivalent to less than 6 cells per 7.5ml of the blood sample or determining the number of CEP17 dots, wherein the circulating cells are isolated from the blood samples using size exclusion methodology that comprises a microfilter, wherein the microfilter has a pore size ranging from about 5-20 microns, wherein the OS and/or PFS is over a period of at least 12 months and wherein the cancer is breast cancer, prostate cancer, lung cancer, pancreatic cancer, kidney cancer or esophageal cancer.
Claims 1-3, 10-12, 15, 20 of Application No. 16/979742 (the ‘742 Application) claim methods for predicting cancer progression in a subject having cancer, comprising determining the size of circulating CAMLs in a blood sample obtained from the subject having cancer, and making a prediction based thereon, wherein when each CAML in the sample is less than about 50um in size, the cancer is predicted not to progress, and wherein when at least one CAML in the sample is about 50um or more in size, the cancer is predicted to progress, and making a treatment decision based on the prediction, wherein when the treatment decision is to administer a cancer treatment, administering a treatment to the subject, wherein CAMLs are isolated from the blood sample using a microfilter having a pore size ranging from about 5-20 microns, wherein the pores of the microfilter have a round, race-track shape, oval, square and/or rectangular pore shape and wherein the cancer is breast cancer, prostate cancer, lung cancer or esophageal cancer.
Claims 1-2, 4-13 and 20-26 of Application No. 17509661 (the ‘661 Application) claims methods of screening a subject of cancer and confirming a diagnosis of cancer in a subject, comprising detecting circulating CAMLs in blood of a subject, wherein the detecting comprises (a) isolating intact cells of 20-300 microns in size from a biological sample obtained from a subject using a means from the group consisting of size exclusion methodology, immunocapture, red blood cell lysis, white blood cell depletion, microfiltration assay comprising high molecular weight polysaccharide separation, electrophoresis, dielectrophoresis, flow, cytometry, magnetic levitation, microfluidic chip and a combination thereof, and (b) selecting multi-nucleated cells isolated in (a) having (i) a large atypical polyploid nucleus of about 14-64um in size or multiple nuclei, and (ii) a morphological shape selected from the group consisting of spindle, tadpole, round, oblong, two legs, more than two legs, and amorphous, thereby detecting CAMLs in the biological sample from a subject, wherein the cancer is breast, prostate, lung, pancreatic or colorectal cancer, wherein when CAMLs are detected in the biological sample, the subject is determined to have a cancer, and the method further comprises administering a cancer treatment to the subject. expressing one or more markers: endothelial cell markers: CD146, CD202b and CD31, and monocyte markers: CD11c and CD14, wherein antibodies are used to select cells expressing the one or more markers thereby detecting CAMLs in the biological sample from a subject, and wherein when CAMLs are detected in the biological sample, the subject is determined to have cancer.
While the claims of the ‘303 Application, the ‘742 Application or the ‘661 Application do not explicitly recite CAMLs in size of ≥ 100mm as indicator of diagnosis of multi organ metastasis and/or multifocal metastatic disease or predicting development of multi-organ metastasis and/or multifocal metastatic disease or OS/PFS in the subject with cancer, Adams et al. (WO2018/151865) teach these limitations and provide motivation and an expectation of success for the reasons set forth above under the 103 rejection. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known finding of the presence of CAMLs in size of ≥ 100mm in cancer patients with stage 4 metastasis to different organs compared to the absence of CAMLs in size of ≥ 100mm in patients with stages 1-3, the known CAML size of ≥ 100mm in cancer patients with stage 4 metastasis to different organs and the known technique disclosed by Adams to the methods of the ‘303 Application, the ‘742 Application or the ‘661 Application, and yield the predictable result of diagnosing multiple organ metastasis and/or multifocal metastatic disease in a subject, predicting development of multiple organ metastasis and/or multifocal metastatic disease in a subject and predicting overall survival (OS) and/or progression free survival (PFS) of a subject having cancer based on determining the size of CAMLs in a biological sample from a subject having cancer and the presence of at least one CAML in size of ≥ 100mm in the biological sample compared to a subject having the same or similar cancer but lacking at least one CAML in a corresponding sample about 100mm or more in size.
This is a provisional nonstatutory double patenting rejection.
Conclusion
NO CLAIM IS ALLOWED.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Adams et al. (PNAS, 2014; 111:3514-3519) teach a method of diagnosing malignant disease based on detecting the presence of CAMLs, wherein the CAMLs are CD14+/CD11c+ with enlarged nuclei, CD45+, CK8+, CK18+, CK19+, EpCAM+ (see abstract; p. 3515-3517).
Augustyn et al. (Clinical Lung Cancer, 2020; 22:e451-65) teach a method of diagnosing or predicting development of metastatic disease or predicting survival of a patient with cancer based on the presence of CAML number and size as an indicator, wherein patients with CAMLs in size larger than 50um have shorter OS than those with CAMLs in size less than 50um and wherein the CAMLs are isolated using CellSieveTM microfilter and filtration system(see abstract; p. 11249, figure 3).
Tang et al. (Cytometry Part A, 2018; 93A:1246-1250) teach a method of diagnosing or predicting development of metastatic disease or predicting survival of a patient with cancer based on the presence of giant CAMLs as an indicator, wherein patients with giant CAMLs develop metastatic disease and had poorer survival compred to those without (see abstract; p. 138).
Adams et al. (Cancer Epidemiol. Biomarkers Prev.; 2016; 25:1037-42) teach a method of diagnosing malignant breast cancer based on the presence of CAMLs as an indicator, wherein patients with CAMLs at baseline had worse PFS and OS compared to patients without CAMLs, wherein the CAMLs are enlarged multinuclear cells with CK8, CK18, CK19, CD45 positive (see abstract; p. 138).
Mu et al. ( Breast Cancer Res. Treat., 2017; 165:733-741) teach a method of predicting overall survival (OS) and/or progression-free survival (PFS) of patients with metastatic breast cancer stage IV (MBC) based on the presence of CAMLs as an indicator, wherein patients with CAMLs at baseline had worse PFS and OS compared to patients without CAMLs, wherein the CAMLs are CD14+/CD11c+ with large atypical nuclei or multiple nucleic, CK8, CK18, CK19, CD45 positive (see abstract).
Zhu et al. (J. Transl. Med. 2016; 14:198. DOI 10.1186/s12967-016-0953-2) teach a method using CellSieveTM microfiltration assay for isolating CTCs and CAMLs from peripheral blood of patients with metastatic renal cell carcinoma (see abstract).
Cassetta et al. (Chapter 12, Isolation of Mouse and Human Tumor-Associated Macrophages, Book: Tumor Microenvironment Study Protocols, edited by Koumenis et al., Springer International Publishing Switzerland 2016) teach a method of isolating mouse and human tumor-associated macrophages (TAMs) by filtering the cells using a 100um cell strainer (p. 220).
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Chang-Yu Wang
June 11, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675
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