DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or
under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application claims benefit of
the foreign application EPO 20168671.4 filed 04/08/2020. Based on the filing receipt, the effective filing date of this application is April 8, 2020 which is the filing date of Application EPO 20168671.4 from which the benefit of priority is claimed.
Status of Claims
Claims 1-8, 10-13, and 15-20 are pending and are examined herein.
Claims 9 and 14 are cancelled.
Withdrawn Rejections
The rejection of claims 1-20 on the grounds of 35 U.S.C. 112(a) is withdrawn, necessitated by amendments filed 11/21/2025. The amendment to claim 1 has reduced the scope of the genus of antibodies encompassed by the claims.
The rejections of claims 6, 9, and 16 on the grounds of 35 U.S.C. 112(b) are withdrawn, necessitated by amendments filed 11/21/2025.
The rejections below have been modified, necessitated by amendments filed 11/21/2025.
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 1-6, 10-13, and 15-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and natural relationships/phenomena without significantly more. The rejection below has been modified, necessitated by amendments filed 11/21/2025.
Under the MPEP, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
Natural Laws:
Claim 1 recites, “determining non-specific clearance of an antibody “ and “whereby non-specific clearance of the antibody is detected if the fluorescence intensity of the primary human endothelial cells determined in step b) is higher than the fluorescence intensity of the primary human endothelial cells determined in the absence of the antibody”. Claim 1 also specifies the antibody has an Fc-region of the human IgG1 or IgG4 subclass. Claim 11 specifies the endothelial cells are primary human liver endothelial cells.
The natural phenomena to which the claims are directed (i.e. non-specific clearance of antibodies, specifically antibodies with Fc-region of the IgG1 or IgG4 subclass, by endothelial cells, specifically primary human liver endothelial cells) are laws of nature. Similar concepts have been held by the courts to constitute law of nature/natural phenomena, as in the identification of a correlation between the presence of biomarkers in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between non-specific clearance of antibodies and endothelial cells. Non-specific clearance of antibodies by endothelial cells occurs in nature without any human action.
The natural phenomenon of non-specific clearance of antibodies by endothelial cells is a judicial exception as it exists in principle apart from any human action; the relationship itself therefore cannot form the basis for eligibility.
Abstract Ideas:
Also, claim 1 is directed towards “determining” non-specific clearance of an antibody and “determining” the fluorescence intensity of the endothelial cells. Claim 2 is directed towards “determining” the fluorescence intensity of cells incubated in the absence of the antibody.
The claim limitation of “determining” non-specific clearance of an antibody or the fluorescence intensity of cells may be categorized as an abstract idea, namely a mental process/concept performed in the human mind. The claims, under its broadest reasonable interpretation, cover performance of determining non-specific clearance or fluorescence intensity solely within the human mind, or by a human using pen and paper. Evaluating or analyzing the results of a method to determine non-specific clearance or fluorescence intensity is performed in the human mind or by a human using pen and paper. Therefore, this determination of non-specific clearance or fluorescence intensity represents an abstract idea.
Step 2A, Prong 2
The above-discussed steps of the determination of non-specific clearance or fluorescence intensity are insufficient to integrate the judicial exception into a practical application because steps corresponding to mental activities, which could be performed in a practitioner’s head, are insufficient to constitute a practical application. In this case, determination of non-specific clearance or fluorescence intensity, represents a judicial exception and not a practical application thereof.
The claims also recite “incubating the antibody, which is conjugated to a pH-sensitive fluorescent dye, with primary human endothelial cells” (claim 1), wherein the incubation step is up to 4 hours (claim 12) and at least 0.5 hours (claim 13). Such steps of incubating antibodies with endothelial cells are insufficient to integrate the judicial exceptions because the purpose is merely to obtain data. This does not go beyond insignificant presolution activity, i.e., a mere data gathering step necessary to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015).
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The additional elements of claims 1-6, 10-13, and 15-16, including the step of washing the endothelial cells (claim 3), do not add significantly more to the judicial exception. Washing cells prior to measuring fluorescence is routine and convention as demonstrated by Nath, et al. (“Homogeneous plate based antibody internalization assay using pH sensor fluorescent dye”, published 2016-04, cited in PTO-892 dated 05/22/2025). Nath teaches the cells are washed prior to the determination of the fluorescence intensity (see, e.g., p. 13, col. 2: “To achieve higher sensitivity, media is replaced by PBS before reading the plate”). It is understood that the replacement of the media with PBS is equivalent to washing. Furthermore, the claims disclose that the antibody is conjugated to a pH-sensitive fluorescent dye (claim 1), which changes fluorescence intensity in response to changes in pH (claims 1 and 4) and has the structure of Formula I (claim 5). The conjugation of pH-sensitive fluorescent dyes with the above-mentioned properties are routine and conventional in the art as demonstrated by Nath. Nath teaches the dye has fluorescence intensity change between a physiological pH of about 7 and an acidic pH in the range of pH 4 to 5 of about 10-fold at the same concentration of the dye excited at the same wavelength (see, e.g., p. 14, under “Fig. 3.”, under panel “A”). The examiner understands that in “Fig. 3.” the normalized fluorescence between pH 4 to pH 5 is about 10-fold of the fluorescence at pH 7. Nath teaches the dye pHAb of Formula I (see, e.g., “Fig. 1.”). The claims disclose that the dye is conjugated to the antibody at residue 297 (claims 6 and 16). The site-specific conjugation of fluorescent dyes to IgG antibodies is routine and conventional in the art as demonstrated by Toftevall, et al. (“Antibody Conjugations via Glycosyl Remodeling”, published 2019-10-24, cited in PTO-892 dated 05/22/2025). Toftevall teaches “the most common therapeutic antibody, human IgG, carry a complex type N-glycan at position N297 of the Fc domain” (see, e.g., p. 131, under “Introduction”). Toftevall teaches the conjugation of N-glycans on the Fc domains of IgGs with click reactions (see, e.g., p. 134, under “Fig. 2”, under panel “a)”). The claims disclose the fluorescent intensity is the geometric mean fluorescent intensity determined by FACS (claim 10). The use of the geometric mean fluorescent intensity determined by FACS is routine and conventional in the art as demonstrated by Bossenmaier (US 20100256339 A1, published 2010-10-07, cited in PTO-892 dated 05/22/2025). Bossenmaier teaches the fluorescent intensity is the geometric mean fluorescence intensity determined by FACS (see, determined by FACS - e.g., p. 27, under “Example 8”, para. [0298]; geometric mean fluorescence intensity - p. 27, under “Example 8”, para. [0299]). The claims disclose the antibody is a bispecific antibody (claim 15). Bispecific antibodies are well-known, routine and conventional in thar art as demonstrated by Bossenmaier. Bossenmaier teaches the antibody is a bispecific antibody (see, e.g., p. 27, under “Example 8”, para. [0299]).
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exceptions.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Bevan, et al. (“Real-Time 96-Well Antibody Internalization Assays Using Incucyte® Fabfluor-pH Antibody Labeling Dye”, published 2017-08, cited in PTO-892 dated 05/22/2025) as evidenced by Idusogie, et al. (“Mapping of the C1q Binding Site on Rituxan, a Chimeric Antibody with a Human IgG1 Fc”, published 2000-04-15, cited in PTO-892 dated 05/22/2025). The rejections below have been modified, necessitated by amendments filed 11/21/2025.
Bevan teaches a method comprising incubating an antibody conjugated to a pH-sensitive fluorescent dye with cells then determining the fluorescence intensity of the cells, wherein the fluorescence intensity of the cells incubated with the antibodies is higher than the fluorescent intensity of cells incubated in the absence of the antibodies when clearance (or antibody internalization) occurs, as in claim 1 (see, e.g., incubating an antibody with cells – p. 4, para. 1; conjugated to a pH-sensitive fluorescent dye – p. 2, under “Assay Principle”: “Fc-region targeting fab fragments conjugated to a pH-sensitive fluorescent probe” and p. 3, under “Quick Guide”; determining fluorescence intensity of the cells incubated with the antibodies and cells incubated in the absence of the antibodies – p. 4, under “Figure 2”, under panel “C.”; when clearance (or antibody internalization) occurs – p. 4, under “Proof of Concept”: “The red signal was observed in the cytosolic compartment of the cells but not in the nucleus, consistent with the expected localization of the internalized antibody to lysosomes and endosomes”). Note: it is assumed that the legend of “Figure 2”, panel “C.” is incorrect based on the description of the assay in p. 4, col. 2 and based on panels “A.” and “B.” of “Figure 2”. Bevan teaches the antibody, Rituxan, has an Fc-region of the human IgG1 subclass, as in claim 1 (see, e.g., p. 8, under “Figure 7”). Bevan teaches the dye has a different fluorescence intensity at physiological pH of about pH 7.4 than at lysosomal pH of about pH 4.5, as in claim 1 (see, e.g., p. 2, under “Figure 1”, panels “B.” and “C.”). Bevan teaches determining the fluorescence intensity of the cells incubated in the absence of the antibody, as in claim 2 (see, e.g., p. 4, under “Proof of Concept”: “A rapid time-dependent increase in red fluorescence was observed with anti-CD71, but not isotype or media control”). The examiner understands the media control to be cells incubated in the absence of the antibodies. Bevan teaches the incubation is for up to 4 hours and at least 0.5 hours, as in claims 12 and 13 (see, e.g., p. 4, under “Figure 2”, under panel “C.”). Rituxan contains an Fc-region of the human IgG1 subclass as evidenced by Idusogie (see, e.g., under “Abstract”).
Bevan does not explicitly teach the method used on endothelial cells for determining non-specific clearance, as in claims 1 and 2. However, Bevan rectifies this deficiency by disclosing that “internalization of antibodies by either specific (target mediated) or non-specific (e.g., pinocytosis in endothelial cells) mechanisms is a key determinant of the half-life in the body” (see, e.g., p. 1, under “Introduction”, para. 1). By disclosing that non-specific clearance occurs in endothelial cells, Bevan renders obvious the use of their method applied to endothelial cells to measure non-specific clearance.
One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use the method of Bevan on endothelial cells to measure non-specific clearance of antibodies. An artisan would have been motivated to use the method of Bevan to measure non-specific clearance of antibodies by endothelial cells because Bevan teaches that “the rate of removal from the cell surface will strongly influence the therapeutic profile of the antibody. More generally, internalization of antibodies by either specific (target mediated) or non-specific (e.g., pinocytosis in endothelial cells) mechanisms is a key determinant of the half-life in the body, and small modifications to monoclonal antibody structure can have profound effects on duration of activity. For these reasons, understanding the internalization of antibodies into cells, and being able to compare the uptake of different antibodies, is a key requirement in antibody selection and optimization for biologics drug discovery” (see, e.g., p. 1, under “Introduction”, para. 2). Also, while the method of Bevan illustrated in p. 4, “Figure 2” can be run up to 12 hours, the difference between the fluorescent intensity of cells with internalized antibodies compared to the fluorescent intensity of cells without the antibodies is high enough to determine which cells have internalized antibodies after only 4 hours (signal to background ratio was >15). During routine optimization, an artisan would have been motivated to decrease the assay run time in order to save time and resources without sacrificing ability to determine antibody clearance. The artisan would have had a reasonable expectation of success based on the disclosure of Bevan.
Claims 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Bevan (cited above), as applied to claims 1-2 and 12-13 above, and further in view of Nath (cited above).
Bevan teaches as set forth above, but fails to teach the cells are washed prior to the determination of the fluorescence intensity, as in claim 3. Bevan fails to teach the dye has fluorescence intensity change between a physiological pH of about 7 and an acidic pH in the range of pH 4 to 5 of about 10-fold at the same concentration of the dye excited at the same wavelength, as in claim 4. Bevan fails to teach the dye pHAb of Formula I, as in claim 5.
However, Nath rectifies these deficiencies in a journal article on an antibody internalization assay using a pH sensor fluorescent dye (see, e.g., p. 11, under “Abstract”). Nath teaches the cells are washed prior to the determination of the fluorescence intensity, as in claim 3 (see, e.g., p. 13, col. 2: “To achieve higher sensitivity, media is replaced by PBS before reading the plate”). Nath teaches the dye has fluorescence intensity change between a physiological pH of about 7 and an acidic pH in the range of pH 4 to 5 of about 10-fold at the same concentration of the dye excited at the same wavelength, as in claim 4 (see, e.g., p. 14, under “Fig. 3.”, under panel “A”). The examiner understands that in “Fig. 3.” the normalized fluorescence between pH 4 to pH 5 is about 10-fold of the fluorescence at pH 7. Nath teaches the dye pHAb of Formula I, as in claim 5 (see, e.g., “Fig. 1.”).
Bevan and Nath are analogous to the field of the claimed invention because they are both in the field of antibody internalization. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the pHAb dye of Nath into the method of Bevan. The artisan would have been motivated to do so because the normalized fluorescence of the pHAb dye of Nath between pH 4 to pH 5 is about 10-fold of the fluorescence at pH 7, but the pHAb dye of Bevan has only a 2-fold increase in normalized fluorescence between pH 4 to pH5 compared to pH 7 (see, e.g., Bevan, p. 2, under “Figure 1”, panel “B”). The artisan would have had a reasonable expectation of success based on the given disclosures.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Bevan (cited above), as applied to claims 1-2 and 12-13 above, in view of Toftevall (cited above).
Bevan teaches as set forth above, but fails to teach the dye is conjugated to the antibody at residue 297 (numbering according to Kabat), as in claim 6.
However, Toftevall rectifies this deficiency in an academic textbook chapter on antibody conjugations at Fc-glycan sites (see, e.g., p. 131, under “Abstract”). Toftevall teaches “the most common therapeutic antibody, human IgG, carry a complex type N-glycan at position N297 of the Fc domain” (see, e.g., p. 131, under “Introduction”). Toftevall teaches the conjugation of N-glycans on the Fc domains of IgGs with click reactions, as in claim 6 (see, e.g., p. 134, under “Fig. 2”, under panel “a)”).
Bevan and Toftevall are analogous to the field of the claimed invention because they are both in the field of bioconjugation. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to replace the conjugation method of Bevan with the conjugation method of Toftevall. The artisan would have been motivated to do so because “[t]he IgG Fc-glycans are of interest as a site for conjugation both because of their location, covered between the Fc domains and far from the antigen binding sites, and their different chemical composition compared to amino acids, making specific chemical modifications possible” (see, e.g., p. 131-132, under “Introduction”). The artisan would have had a reasonable expectation of success based on the given disclosures.
Claims 10 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Bevan (cited above), as applied to claims 1-2 and 12-13 above, in view of Bossenmaier (cited above).
Bevan teaches as set forth above, but fails to teach the fluorescent intensity is the geometric mean fluorescence intensity determined by fluorescence-activated cell sorting (FACS), as in claim 10. Bevan fails to teach the antibody is a bispecific antibody, as in claim 15.
However, in a patent application publication on bispecific antibodies, Bossenmaier rectifies these deficiencies. Bossenmaier teaches the fluorescent intensity is the geometric mean fluorescence intensity determined by FACS, as in claim 10 (see, determined by FACS - e.g., p. 27, under “Example 8”, para. [0298]; geometric mean fluorescence intensity - p. 27, under “Example 8”, para. [0299]). Bossenmaier teaches the antibody is a bispecific antibody, as in claim 15 (see, e.g., p. 27, under “Example 8”, para. [0299]).
Bevan and Bossenmaier are analogous to the field of the claimed invention because they are both in the field of antibody internalization assays. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the mean fluorescence intensity by FACS and bispecific antibodies of Bossenmaier into the method of Bevan. An artisan would have been motivated to do so because using FACS would allow the artisan to sort between cells that have internalized the antibodies and cells that have not internalized the antibodies for further study. In addition, an artisan would have been motivated to do so because “bispecific antibodies are reported that can be efficiently expressed in prokaryotic and eukaryotic cells, and are useful in therapeutic and diagnostic methods” (see, e.g., p. 2, para. [0014]). An artisan would have had a reasonable expectation of success based on the given disclosures.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Bevan (cited above), as applied to claims 1-2 and 12-13 above, in view of Bowdish (US 20050281828 A1, published 2005-12-22, cited in PTO-892 dated 05/22/2025) and Eigenmann, et al. (“Quantification of IgG monoclonal antibody clearance in tissues”, published 2017-07-27, cited in PTO-892 dated 05/22/2025) as evidenced by the Human Liver-Derived Endothelial Cells product information from Lonza (https://bioscience.lonza.com/lonza_bs/US/en/ADME-and-Toxicology/p/000000000000253232/Human-Liver-Derived-Endothelial-Cells-P1, cited in PTO-892 dated 05/22/2025).
Bevan teaches as set forth above, but fails to teach the cells are primary human liver endothelial cells, as in claim 11.
However, Eigenmann and Bowdish rectify this deficiency. Eigenmann, in a journal article titled “Quantification of IgG monoclonal antibody clearance in tissues”, discloses that the liver has the highest rate of “[u]nspecific total tissue clearance” (see, e.g., p. 1007, under “ABSTRACT”). Bowdish, in a patent application publication on a method of treating autoimmune disease with antibodies to antigen-presenting cells (see, e.g., cover page, under “ABSTRACT”), teaches an antibody internalization assay with primary human liver endothelial cells, as in claim 11 (see, e.g., antibody internalization assay with liver endothelial cells – p. 4, col. 1, para. [0048]; primary human liver endothelial cells – p. 17, col. 2, para. [0161). Liver sinusoidal endothelial cells are a species of the genus liver endothelial cells as evidenced by the Human Liver-Derived Endothelial Cells product information from Lonza.
Bevan, Eigenmann, and Bowdish are analogous to the field of the claimed invention because they are all in the field of antibody clearance. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the cells of Bowdish into the method of Bevan. An artisan would have been motivated to do so because Eigenmann discloses that the liver is the organ with the highest rate of unspecific clearance. An artisan would have had reasonable expectation of success based on the given disclosures.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Bevan (cited above) and Nath (cited above), as applied to claims 3-5, and further in view of Toftevall, et al. (“Antibody Conjugations via Glycosyl Remodeling”, published 2019-10-24, cited in PTO-892 dated 05/22/2025).
Bevan and Nath teach as set forth above, but fails to teach the dye is conjugated to the antibody at residue 297 (numbering according to Kabat), as in claim 16.
However, Toftevall rectifies this deficiency in an academic textbook chapter on antibody conjugations at Fc-glycan sites (see, e.g., p. 131, under “Abstract”). Toftevall teaches “the most common therapeutic antibody, human IgG, carry a complex type N-glycan at position N297 of the Fc domain” (see, e.g., p. 131, under “Introduction”). Toftevall teaches the conjugation of N-glycans on the Fc domains of IgGs with click reactions, as in claim 16 (see, e.g., p. 134, under “Fig. 2”, under panel “a)”).
Bevan, Nath, and Toftevall are analogous to the field of the claimed invention because they are both in the field of bioconjugation. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to replace the conjugation method of Bevan and Nath with the conjugation method of Toftevall. The artisan would have been motivated to do so because “[t]he IgG Fc-glycans are of interest as a site for conjugation both because of their location, covered between the Fc domains and far from the antigen binding sites, and their different chemical composition compared to amino acids, making specific chemical modifications possible” (see, e.g., p. 131-132, under “Introduction”). The artisan would have had a reasonable expectation of success based on the given disclosures.
Response to Arguments
The applicant argues that the amendments to independent claim 1 render the application readily commensurate with the scope of the presently amended claims. The remaining claims 2-8, 10-13, and 15-20 depend from claim 1. The office agrees and has withdrawn the 35 U.S.C. 112(a) rejections of claims 1-8, 10-13, and 15-20 as stated above.
The applicant argues that the amendments to claims 6, 9, and 16 render the 35 U.S.C. 112(b) rejections moot. The office agrees and has withdrawn the rejections in response to the amendments.
The applicant argues that the present amendments to claim 1 render the 35 U.S.C. 101 rejection moot. However, the amendments do not add significantly more to the judicial exception. The use of an antibody comprising an Fc-region of a human IgG1 or IgG4 subclass is routine and convention, as stated above. The use of a dye with a different fluorescent intensity at a pH of about 7.4 than at a pH of about 4.5 is routine and convention, as stated above. Therefore, the 35 U.S.C. 101 rejection of claims 1-6, 10-13, and 15-16 is maintained.
The applicant argues that the present amendments render the 35 U.S.C. 103 rejections moot. They argue that no cited reference, individually or in combination, discloses, teaches or suggests the present invention wherein the antibody comprises an Fc-region of a human IgG1 or IgG4 subclass and wherein the dye has different fluorescence intensity or emission wavelengths at physiological pH of about pH 7.4 and at lysosomal pH of about pH 4.5. However, as discussed above, the cited references disclose these claim limitations. Therefore, the 35 U.S.C. 103 rejections have been maintained.
Conclusion
Claims 7-8 and 17-20 are allowed.
Claims 1-6, 10-13, and 15-16 are rejected.
The following is an examiner’s statement of reasons for allowance:
The prior art of record does not teach or make obvious the linker of Formula II and/or the dye of Formula III, as disclosed in p. 8-9 of the applicant’s application.
The closest art of record is Bevan (cited above) as evidenced by Idusogie (cited above). Bevan teaches a method comprising incubating an antibody conjugated to a pH-sensitive fluorescent dye with cells then determining the fluorescence intensity of the cells, wherein the fluorescence intensity of the cells incubated with the antibodies is higher than the fluorescent intensity of cells incubated in the absence of the antibodies when clearance (or antibody internalization) occurs, as in claim 1 (see, e.g., incubating an antibody with cells – p. 4, para. 1; conjugated to a pH-sensitive fluorescent dye – p. 2, under “Assay Principle”: “Fc-region targeting fab fragments conjugated to a pH-sensitive fluorescent probe” and p. 3, under “Quick Guide”; determining fluorescence intensity of the cells incubated with the antibodies and cells incubated in the absence of the antibodies – p. 4, under “Figure 2”, under panel “C.”; when clearance (or antibody internalization) occurs – p. 4, under “Proof of Concept”: “The red signal was observed in the cytosolic compartment of the cells but not in the nucleus, consistent with the expected localization of the internalized antibody to lysosomes and endosomes”). Note: it is assumed that the legend of “Figure 2”, panel “C.” is incorrect based on the description of the assay in p. 4, col. 2 and based on panels “A.” and “B.” of “Figure 2”. Bevan teaches the antibody, Rituxan, has an Fc-region of the human IgG1 subclass, as in claim 1 (see, e.g., p. 8, under “Figure 7”). Bevan teaches the dye has a different fluorescence intensity at physiological pH of about pH 7.4 than at lysosomal pH of about pH 4.5, as in claim 1 (see, e.g., p. 2, under “Figure 1”, panels “B.” and “C.”). Rituxan contains an Fc-region of the human IgG1 subclass as evidenced by Idusogie (see, e.g., under “Abstract”). However, Bevan fails to teach the linker of Formula II and/or the dye of Formula III, as disclosed in p. 8-9 of the applicant’s application.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL C SVEIVEN whose telephone number is (703)756-4653. The examiner can normally be reached Monday to Friday - 8AM to 5PM PST.
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/MICHAEL CAMERON SVEIVEN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678