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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/14/2025 has been entered.
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.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are: “a component for incubating”, “a component for washing”, “a component for detecting”, and “a component for purifying” in claims 43 and 46.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
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 43 and 46 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim limitations “a component for incubating”, “a component for washing”, “a component for detecting”, and “a component for purifying” invoke 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 insufficient disclosure of the corresponding structures since a "component" is broadly defined and includes any suitable apparatus or collection of apparatuses suitable for carrying out the recited method (Para. 0082). 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.
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.
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 43, 45, 46, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al, (CA2905798A1, of record), hereinafter Chen, in view of Brown et al (Brown, Jeremy K., et al. Journal of Histochemistry & Cytochemistry 52.9 (2004): 1219-1230, of record), hereinafter Brown.
Chen teaches a method for determining likelihood that a subject with a disease or disorder will benefit from anti-PD-L1 treatment, comprising detecting the presence of a PD-L1 biomarker in a tumor tissue sample obtained from the subject, wherein the presence of PD-L1 biomarker in the cancer sample is determined by measuring protein expression (such as using immunohistochemistry protocols) and indicates that the subject has an increased likelihood of benefit from (and is thus suitable for) treatment with an PD-L1 antagonist such as a human anti-PD-L1 antibody (see entire document, in particular, Abstract, Summary, Claims, Para. 008-0010, Para. 0026, Para. 0031, Para. 00205, Para. 00218). As such, it follows that if PD-L1 is not expressed in a sample obtained from the subject, then said subject will not have benefit from (and is thus not suitable for) anti-PD-L1 treatment. In particular, the method of determining the presence, expression, level, or amount of a protein in a biological sample comprises contacting the biological sample with antibodies to a biomarker (e.g. anti-PD-L1 antibodies) described in the disclosure of Chen and detecting whether a complex is formed between the antibodies and biomarker (Para. 0217). Additionally, “an anti-PD-L1 antibody” or “an antibody that binds to PD-L1” refers to an antibody that is capable of binding PD-L1 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting PD-L1 (Para. 00112). Thus, the anti-PD-L1 antagonists which are used for treatment of a subject with cancer can also be used as a detection reagent for determining the likelihood that a subject would benefit from treatment with said anti-PD-L1 antagonists.
Chen does not teach that the immunohistochemistry to detect PD-L1 biomarker expression in a biological sample obtained from a subject utilizes purified preformed immune complexes of primary and secondary antibodies.
However, Brown teaches a method by which primary antibodies can be non-covalently labeled in vitro with a reporter molecule using monovalent Fab fragments that recognize both the Fc and F(ab’)2 regions of IgG. Primary antibodies maintain their affinity for specific antigen after labeling with Fab fragments in vitro. Incubation of these immune complexes with excess normal serum from the same species as the primary antibody prevents free Fab fragments from recognizing immunoglobulin(see Abstract and Discussion on Page 1228, first paragraph). Specifically, while the sample is blocked with 10% normal mouse serum, primary mouse antibody is incubated for 20 min with fluorescent anti-mouse Fab fragments. The resultant primary antibody–Fab fragment complexes are incubated with excess normal mouse serum for 10 min to block free Fab fragment paratopes, diluted to working concentration, and centrifuged before use to remove any insoluble precipitates (Figure 1). Thus, prior to incubation with a biological sample, the preformed immune complexes are purified via centrifugation. Primary mouse antibody–Fab fragment complexes are then applied to the sample, resulting in specific labeling in the absence of spurious cross-reactions with endogenous mouse IgG (Figure 1). After incubation with the primary antibody-Fab complexes, the sample is washed (see “Primary Antibody-Fab Fragment Complex Formation Kinetics” section). In particular, triple-color immunofluorescent labeling of frozen sections from normal mouse jejunum was carried out with Fab fragment complexes containing primary antibodies derived from the same host species pre-labeled with fluorophore-conjugated anti-rat IgG Fab fragments (see Figure 4 Results, beginning on Page 1224, Left Column). Using complexes containing Fab fragments that recognize both the Fc and F(ab')2 regions of IgG, this approach prevents nonspecific labeling of endogenous immunoglobulin, can be used to simultaneously detect multiple antigens with primary antibodies derived from the same species, and allows the same polyclonal antibody to be used for both antigen capture and detection in ELISA. The steps of the method (purification of preformed complexes, incubation of preformed complexes with sample, washing of sample, detection of complexes) are all necessarily performed by or with the use of equipment, devices, systems, apparatuses and/or machines (i.e. components) as recited in instant claims 43 and 46. For example, the incubation of the primary-Fab antibody complexes with sample and washing of the sample can be carried out using microtiter plates (see “Primary Antibody-Fab Fragment Complex Formation Kinetics” section). Thus, the microtiter plates can act as components for incubating and washing. The primary antibody-Fab complexes can also be purified by centrifugation, which would require the use of a centrifuge (i.e. a component for purifying). The reaction of the primary-antibody Fab complexes and sample can be detected using a fluorescent microscope (i.e. a component for detecting) (see, e.g. “Microscopy and Imaging” section).
It would have been obvious to one of ordinary skill in the art to modify the method of identifying a subject suitable for anti-PD-L1 treatment disclosed by Chen such that purified preformed immune complexes as taught by Brown are used to detect a PD-L1 biomarker in a biological sample taken from the subject. One of ordinary skill in the art would have been motivated to do so since the preformed immune complexes prevent nonspecific labeling of endogenous immunoglobulin. Therefore, one of ordinary skill in the art would expect using purified pre-formed immune complexes in the method of Chen can effectively identify a subject suitable for treatment with a therapeutic agent, in this case, anti-PD-L1 antibody.
Claims 43, 45, 46, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al, (CA2905798A1, of record), hereinafter Chen, in view of Hamann et al (US8093012B2, of record), hereinafter Hamann.
Chen teaches a method for determining likelihood that a subject with a disease or disorder will benefit from anti-PD-L1 treatment, comprising detecting the presence of a PD-L1 biomarker in a tumor tissue sample obtained from the subject, wherein the presence of PD-L1 biomarker in the cancer sample is determined by immunohistochemistry and indicates that the subject has an increased likelihood of benefit from (and is thus suitable for) treatment with an PD-L1 antagonist such as a human anti-PD-L1 antibody (see entire document, in particular, Abstract, Summary, Claims, Para. 008-0010, Para. 0026, Para. 0031, Para. 00205, Para. 00218). As such, it follows that if PD-L1 is not expressed in a sample obtained from the subject, then said subject will not have benefit from (and is thus not suitable for) anti-PD-L1 treatment. In particular, the method of determining the presence, expression, level, or amount of a protein in a biological sample comprises contacting the biological sample with antibodies to a biomarker (e.g. anti-PD-L1 antibodies) described in the disclosure of Chen and detecting whether a complex is formed between the antibodies and biomarker (Para. 0217). Additionally, “an anti-PD-L1 antibody” or “an antibody that binds to PD-L1” refers to an antibody that is capable of binding PD-L1 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting PD-L1 (Para. 00112). Thus, the anti-PD-L1 antagonists which are used for treatment of a subject with cancer can also be used as a detection reagent for determining the likelihood that a subject would benefit from treatment with said anti-PD-L1 antagonists.
Chen does not teach that the immunohistochemistry to detect PD-L1 biomarker expression in a biological sample obtained from a subject utilizes purified preformed immune complexes of primary and secondary antibodies.
However, Hamann teaches a method of in situ immunohistochemistry for the detection of one or more antigens in a biological sample for diagnosis and prognosis of a disease such as cancer, wherein the sample is a tissue sample (Abstract and Summary of Invention). The methods disclosed utilize antigen retrieval and autofluorescence removal techniques of fluorescent in situ hybridization that allow for highly sensitive immunohistochemical detection of multiple target antigens in tissue samples (Col. 3, Ln. 13-21). Particularly, in some embodiments, a detection reagent specific for a target (or epitope) is saturated with labeling reagent to create a pre-formed complex (Column 17, Ln. 1-18). The detection reagent is a monoclonal antibody or fragment thereof specific for the target of interest; and the labeling reagent is an antibody or fragment thereof comprising a detectable label (e.g. a fluorescent moiety, a radioactive moiety, or enzyme) and binds to the Fc region of the target-binding antibody (i.e. detection reagent) (Col.9, Ln. 66-67 to Col 10. Ln. 1-24; Col. 5, Ln.37-42; Col. 10, Ln. 56-67 to Col. 11, Ln.1- 20). Typically, the labeling reagents comprise a monovalent antibody fragment (Fab) that binds to the Fc and/or F(ab') portion of primary antibody and is covalently or non-covalently attached to a fluorescent label. The Fab fragment or F(ab’) fragment has a greater potential to penetrate formalin-fixed paraffin embedded tissue compared to bivalent secondary antibodies (Col. 5, Ln. 43-50). After complex formation, the mixture is purified to remove un-complexed detection reagent and labeling reagent. For example, excess labeling reagent is removed after the formation of the pre-formed complex e.g. by gel filtration. The purified pre-formed complex is then contacted to a biological sample. Excess pre-formed complex can be removed from the sample in an additional wash step (Column 17, Ln. 1-18). The steps of the method (purification of preformed complexes, incubation of preformed complexes with sample, washing of sample, detection of complexes) are all necessarily performed by or with the use of equipment, devices, systems, apparatuses and/or machines (i.e. components) as recited in instant claim 43. For example, the pre-formed complexes can be incubated with the sample with agitation (e.g. shaking or rocking) and the sample washed (with shaking/rocking) in containers with PBS (Col. 16. Ln.31-37). Thus, the containers can serve as components for incubation and washing of the sample. The labeled pre-formed complexes can be detected by an appropriate detection system such as a fluorescent microscope (Col. 3, Ln. 29-31 and Col. 15, Ln. 43-67 to Col. 16. Ln. 1-10). Thus, the fluorescent microscope can serve as a component for detecting the preformed complexes. The pre-formed complexes as discussed above can be purified via gel filtration which would require the use of a gel filtration apparatus (i.e. a component for purifying).
It would have been obvious to one of ordinary skill in the art to modify the method of identifying a subject suitable for anti-PD-L1 treatment disclosed by Chen such that purified preformed immune complexes as taught by Hamman are used to detect a PD-L1 biomarker in a biological sample taken from the subject, wherein the preformed immune complex comprises a primary antibody linked to a Fab fragment that is conjugated to a detectable label. One of ordinary skill in the art would have been motivated to do so since the methods of Hamman allow for highly sensitive immunohistochemical detection of target antigens in tissue samples and the preformed immune complexes comprising a secondary antibody (labeling regent) that is an antibody fragment such as Fab, which can effectively penetrate formalin-fixed paraffin embedded tissue. Therefore, one of ordinary skill in the art would expect using purified pre-formed immune complexes in the method of Chen can effectively identify a subject suitable for treatment with a therapeutic agent, in this case, anti-PD-L1 antibody.
Response to Arguments
Applicant's arguments filed 07/14/2025 have been fully considered but they are not persuasive.
With respect to the rejections made under 35 U.S.C. 103, Applicant argues that Chen dos not teach the use of therapeutic monoclonal antibodies to determine whether a subject with cancer expresses an epitope of interest targeted by the therapeutic monoclonal antibody (mAb) and is thus suitable for treatment with the therapeutic monoclonal antibody. Further, Tuson does not teach 1) purifying pre-formed complexes prior to staining and 2) the use of therapeutic mAbs to determine whether a subject with cancer expressing an epitope of interest targeted by the therapeutic mAb and is thus suitable for treatment with the therapeutic mAb. Further, Tuson teaches the use of normal human serum (NHS) which can cause non-specific staining. Therefore, artisans would not look to Tuson to develop a method to identify a subject having cancer as suitable for treatment with a therapeutic mAb targeting an epitope of interest, alone or in combination with Chen, Brown, and/or Hamman.
Brown also teaches the need for excess NHS and thus does not rectify the deficiencies of Tuson. Brown fails to teach purified antibody complexes, fails to teach the use of therapeutic mAb to determine treatment suitability, and teaches the use of methods that would increase the incidence of false positives.
Lastly, Hamman discourages the use of preformed Ab complexes like those claimed for reasons including resultant crosslinked complexes and the large size of the complex restricting or inhibiting detection of target molecules. Thus, artisans would not have been motivated to combine Hamman with Tuson and/or Brown. Hamman also fails to teach the use of therapeutic mAb to identify subjects suitable for treatment with the therapeutic mAb.
In response to applicant's argument, the Examiner notes that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, the Examiner reiterates that Chen teaches a method for identifying a subject with cancer suitable for anti-PD-L1 treatment, comprising determining the presence of a PD-L1 biomarker in a sample obtained from the subject, wherein the presence of PD-L1 biomarker in the sample is determined by immunohistochemistry and indicates that subject has an increased likelihood of benefit from treatment with an PD-L1 antagonist such as a human anti-PD-L1 antibody. Moreover, “an anti-PD-L1 antibody” or “an antibody that binds to PD-L1” refers to an antibody that is capable of binding PD-L1 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting PD-L1 (see Para. 00112 of Chen). Additional, in para. 00217 of Chen, it is stated that “the method [of determining the presence, expression, level, or amount of a protein) comprises contacting the biological sample with antibodies to a biomarker (e.g. anti-PD-L1 antibodies) described herein”. The anti-PD-L1 antibodies disclosed by Chen include anti-PD-L1 antagonists that are used as therapeutic agents in the treatment of cancer. As such, the anti-PD-L1 antibody used in the methods of determining the presence of a PD-L1 biomarker in a biological sample can be used as both a detection and therapeutic agent and thus aid in the identification of subjects that would benefit from treatment with said anti-PD-L1 antibody.
Further, Hamann teaches a method of in situ immunohistochemistry for the detection of one or more antigens in a biological sample for diagnosis and prognosis of a disease such as cancer, wherein purified preformed complexes of primary and secondary antibodies can be used for detection of said antigens. While Hamman discusses the drawbacks of other methods that use preformed complexes due to the increased size of the complexes, the methods disclosed in Hamman do not rule out the use of preformed complexes, wherein the secondary antibody (labeling regent) is an antibody fragment such as Fab that can effectively penetrate formalin-fixed paraffin embedded tissues (Col. 5, Ln. 43-50). Hamman also highlights that the methods disclosed utilize the antigen retrieval and autofluorescence techniques of fluorescent in situ hybridization to allow for highly sensitive immunohistochemical detection of target antigens in tissue samples (Col. 3, Ln. 13-21) thus overcoming the limitations of techniques known in the art.
While Brown teaches the use of excess NHS, it is noted that the claimed methods recite the term “comprising” which is open-ended and does not exclude the addition of unrecited elements or steps (MPEP 2111.03). Thus, the method of Brown still read on the instantly claimed methods.
Thus, artisans would be motivated to modify the method of Chen such that purified preformed immune complexes as taught by Hamman or Brown can be used to identify PD-L1 biomarkers in a biological sample in order to identify subjects suitable for anti-PD-L1 treatment, wherein the preformed complex comprises a primary antibody that can be used as both the detection antibody and therapeutic antibody. Thus, the combined teachings of Chen and Hamman/Brown render obvious the instantly claimed invention.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641