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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/09/2026 has been entered.
Priority
This application is a U.S. National Stage (371) application of PCT/US20/16075 filed on 01/31/2020 which claims priority to U.S. Provisional Application No. 62/799,943 filed on 02/01/2019 and to U.S. Provisional Application No. 62/799,363 filed on 01/31/2019.
Claim Status
Claim 1 is currently amended, and the Applicant notes that no new matter is added. Claims 2, 4, 9-10 and 13-14 are original. Claims 3, 5-8, 11-12 and 15 are previously presented.
Claims 16-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/09/2024.
Claims 21-28 are cancelled by the Applicant.
Thus, claims 1-15 are under examination.
Withdrawn Rejections
The previous rejection of claims 1, 3-6 and 8-15 under 35 U.S.C. 103 as being unpatentable over Palmer et al. (US 2014/0004622 A1) and Gornik et al. (Clinical Biochemistry, 40 (2007), 718–723) is withdrawn in light of Applicant’s amendments of claim 1. Specifically, the Applicant amended claim 1 to recite “centrifuging the product of step a) so as to separate and obtain conjugates of transferrin bound
to transferrin-binding antibodies conjugated to nanoparticles, wherein the obtained conjugates of
transferrin bound to transferrin-binding antibodies conjugated to nanoparticles are contained in a
precipitate”. Palmer does not suggest centrifuging before contacting the conjugates with the lectin and thus, the limitation of centrifuging the product of step a) so as to separate and obtain conjugates of transferrin bound to transferrin-binding antibodies conjugated to nanoparticles before contacting the lectin is not taught by Palmer.
The previous rejection of claims 2 and 7 under 35 U.S.C. 103 as being unpatentable over Palmer et al. (US 2014/0004622 A1), Gornik et al. (Clinical Biochemistry, 40 (2007), 718–723) and Remington et al. (US 2004/0002168 A1) is withdrawn in light of Applicant’s amendments of claim 1, onto which claims 2 and 4 depends, as previously discussed.
New Rejections
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 (PHOSITA) to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3-6 and 8-15 are rejected under 35 U.S.C. 103 as being unpatentable over Palmer et al. (US 2014/0004622 A1) in view of Kelly et al. (Nature Nanotechnology, Vol 10, May 2015, pages 472-479) and Gornik et al. (Clinical Biochemistry, 40 (2007), 718–723).
Claim 1 recites:
“A method of detecting asialo-transferrin in a biological sample comprising:
a) contacting the biological sample with a first plurality of transferrin-binding antibodies
conjugated to nanoparticles, wherein the sialic acid residues on glycan chains of the first
plurality transferrin-binding antibodies have been oxidized;
b) centrifuging the product of step a) so as to separate and obtain conjugates of transferrin bound to transferrin-binding antibodies conjugated to nanoparticles, wherein the obtained conjugates of transferrin bound to transferrin-binding antibodies conjugated to nanoparticles are contained in a precipitate;
c) contacting the conjugates obtained in step b) with a lateral flow device, and observing if
asialo-transferrin bound antibodies bind to a second plurality of transferrin-binding antibodies
affixed to the lateral flow device., wherein if such antibodies bind then asialo-transferrin has been detected in the biological sample and wherein if no asialo-transferrin bound antibodies bind to the second plurality of transferrin-binding antibodies affixed to the lateral flow device then asialo-transferrin has not been detected in the biological sample, and wherein the lateral flow device comprises in sequential order:
- a portion comprising a fixed sialic acid-specific lectin; and
- a portion comprising a second plurality of transferrin-binding antibodies affixed to the
lateral flow device; and
- a portion comprising a plurality of anti-antibody antibodies affixed to the lateral flow
device”.
Regarding claim 1, Palmer teaches a method of detecting cerebrospinal fluid (CSF) in a sample by detecting asialo-transferrin in a biological sample that has been depleted of beta-1 transferrin (Abstract; page 2, [0024]).
Palmer teaches contacting the biological sample with a first plurality of transferrin-binding antibodies conjugated to nanoparticles on a lateral flow device (Page 5, [0043] and [0045]).
Palmer teaches contacting conjugates of transferrin bound antibodies on nanoparticles with a lateral flow device, and observing if asialo-transferrin bound antibodies bind to a second plurality of transferrin-binding antibodies affixed to the lateral flow device, wherein if such antibodies bind then asialo-transferrin has been detected in the biological sample and wherein if no asialo-transferrin bound antibodies bind to the second plurality of transferrin-binding antibodies affixed to the lateral flow device then asialo-transferrin has not been detected in the biological sample (Pages 7-8, [0071]; page 11, claim 1).
Palmer teaches that the lateral flow device comprises a portion comprising a fixed sialic acid-specific lectin (Abstract; page 2, [0024]; page 4, [0036] and [0038]; pages 6-7, [0062]).
Palmer teaches that the lateral flow device comprises a second plurality of transferrin-binding antibodies affixed to the lateral flow device (Page 4, [0036]; page 5, [0043] and [0048]).
Palmer teaches that the lateral flow device comprises a portion comprising a plurality of anti-antibody antibodies affixed to the lateral flow device (Page 5, [0046] and [0049]). A skilled artisan would have understood that Palmer offers one of two options: either to deplete the sample of beta-1 transferrin before loading the sample or deplete the sample of beta-1 transferrin while on the pad (Page 3, [0033], “The incubation to form the beta-1 transferrin-lectin conjugate can occur in a separate container, for example, in a tube or other similar container, before the sample is transferred to the sample pad comprising the membrane…” or “The incubation to form the beta-1 transferrin-lectin conjugate can occur in or on the sample pad comprising the membrane.”).
Regarding claim 3, Palmer teaches that each antibody of the second plurality of transferrin-binding antibodies is conjugated to a nitrocellulose membrane of the lateral flow device (Page 4, [0036]; page 5, [0043] and [0048]).
Regarding claim 4, Palmer teaches that multiple antibodies of the first plurality of transferrin-binding antibodies conjugated to nanoparticles are conjugated to the same nanoparticle (Page 4, [0041]; Page 5, [0043]; page 6, [0059]; page 8, [0075]).
Regarding claim 5, Palmer teaches that the nanoparticles comprise gold nanoparticles (Page 5, [0043] and [0046]; page 8, [0075]).
Regarding claim 6, Palmer teaches that the lateral flow device further comprises a fluid sample pad prior in sequential order to the portion comprising a first plurality of transferrin-binding antibodies (Page 1, [0006]; page 3, [0033]; page 4, [0036]; page 5, [0046]).
Regarding claim 11, Palmer teaches that the portion comprising a plurality of anti-antibody antibodies affixed to the lateral flow device is a control line (Page 6, [0051]; page 7, [0068]).
Regarding claim 12, Palmer teaches a kit comprising a separation section and a lateral flow immunoassay section (Page 1, [0007]; page 2, [0021]).
Palmer teaches a container comprising the first plurality of transferrin-binding antibodies conjugated to nanoparticles (Page 2, [0021]; page 5, [0043] and [0046]).
Regarding claim 15, Palmer teaches that the nanoparticles comprise gold nanoparticles (Page 5, [0043] and [0046]; page 8, [0075]).
Regarding claim 1, Palmer does not teach centrifuging the product of conjugates of transferrin bound to transferrin-binding antibodies conjugated to nanoparticles. And Palmer does not teach that the obtained conjugates of transferrin bound to transferrin-binding antibodies conjugated to nanoparticles are contained in a precipitate.
Regarding claims 1, 8 and 13, Palmer does not teach that the sialic acid residues on glycan chains of the transferrin-binding antibodies or the first plurality of the transferrin-binding antibodies have been oxidized.
Regarding claims 9 and 14, Palmer does not teach that the transferrin-binding antibodies which have had their sialic acid residues oxidized show reduced binding to sialic acid-specific lectin compared to transferrin-binding antibodies which have not had their sialic acid residues oxidized.
Regarding claim 10, Palmer does not teach that the transferrin-binding antibodies have been oxidized by treating them with a periodate.
Regarding claim 1, Kelly teaches using antibody-labelled gold nanoparticles, and differential centrifugal sedimentation to study proteins (Abstract). Kelly further teaches centrifuging the product of conjugates of protein-bound transferrin conjugated to nanoparticles (Page 478, right column, third paragraph). Kelly teaches that the obtained conjugates of proteins bound to transferrin conjugated to nanoparticles are contained in a precipitate and are washed by centrifugation and redispersion in phosphate buffered saline (PBS) for later analysis (Page 478, right column, third paragraph).
Regarding claims 1, 8 and 13, Gornik teaches how to oxidize the sialic acid residues on glycan chains of the transferrin-binding antibodies (Page 720, right column, second and third paragraph, “To prevent this, we decided to use deglycosylated antibodies … we developed a method for in situ deglycosylation of IgG”, “20 mmol/L periodate was practically 100% efficient in eliminating binding of SNA lectin to antibodies (indicating destruction of all sialic acid on the antibodies)”).
Regarding claims 9 and 14, Gornik teaches the transferrin-binding antibodies which have had their sialic acid residues oxidized show reduced binding to sialic acid-specific lectin compared to transferrin-binding antibodies which have not had their sialic acid residues oxidized (Page 720, right column, third paragraph, “20 mmol/L periodate was practically 100% efficient in eliminating binding of SNA lectin to antibodies (indicating destruction of all sialic acid on the antibodies)”).
Regarding claim 10, Gornik teaches that the transferrin-binding antibodies have been oxidized by treating them with a periodate (Page 720, right column, third paragraph, “we developed a method for in situ deglycosylation of IgG”, “20 mmol/L periodate was practically 100% efficient in eliminating binding of SNA lectin to antibodies”).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the centrifugation method of Kelly with the asialo-transferrin detection method of CSF leakage of Palmer because Kelly teaches to wash the particles to remove any excess immunogold labels (Page 478, right column, first paragraph) and to maintain the high quality of gold nanoparticle–antibody conjugates (page 472, right column, first paragraph). A skilled artisan would have been further motivated to combine glycan oxidation method of antibodies of Gornik with the combined methods of Kelly and Palmer because Gornik noted that if the glycan part of native antibodies is not oxidized, the lectins would bind not only to glycans on transferrin but also to glycans of immunoglobulins which interferes with the assay results (Page 720, right column, second and third paragraph). A skilled artisan would have been motivated to combine the above methods to produce a method that specifically detect a marker of cerebrospinal leakage. It would have been obvious for a PHOSITA to use the centrifugation method of Kelly and the antibody oxidation method of Gornik in the asialo-transferrin method of Palmer to achieve a better differential diagnosis and detection of cerebrospinal fluid leakage.
A PHOSITA would have had a reasonable expectation of success in combining the methods of
Kelly, Gornik and Palmer based on the methods being in the field of detecting a target antigen in body fluids by immunoassays.
Claims 2 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Palmer et al. (US 2014/0004622 A1), Kelly et al. (Nature Nanotechnology, Vol 10, May 2015, pages 472-479) and Gornik et al. (Clinical Biochemistry, 40 (2007), 718–723) as applied to claim 1 above, and further in view of Remington et al. (US 2004/0002168 A1).
Claim 2 recites:
“The method of Claim 1, wherein the first and second pluralities of transferrin-binding
antibodies are IgG antibodies and/or wherein the plurality of anti-antibody antibodies is
a plurality of anti-IgG antibodies”.
Regarding claims 2 and 7, the teachings of Palmer, Kelly and Gornik are previously discussed.
Regarding claims 2, Palmer does not teach that the first and second pluralities of transferrin binding antibodies are IgG antibodies and/or the plurality of anti-antibody antibodies is a plurality of anti-IgG antibodies.
Regarding claim 7, Palmer does not teach that the lateral flow device further comprises a fluid-absorbent pad subsequent in sequential order to the portion comprising a plurality of anti-antibody antibodies. Palmer still offers material to serve for absorption of fluid (Page 5, [0047]; page 6, [0054]). Furthermore, Palmer offers an absorption pad to be used for introducing a sample to the test surface (Page 6, [0060]).
Regarding claim 2, Remington teaches that the antibodies used to bind transferrin are IgG (Page 1, [0019]).
Regarding claim 7, Remington teaches that the lateral flow device further comprises a fluid-absorbent pad subsequent in sequential order to the portion comprising a plurality of anti-antibody antibodies (Sheet 4 of 10, FIG. 4, “470”; page 8, [0090], “The strip test may also comprise an absorbent pad 470, which is contiguous with the lateral flow membrane”).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the IgG antibodies of Remington with the combined methods of Kelly, Gornik and Palmer to improve the detection of cerebrospinal fluid leakage in a sample by using asialo-transferrin because Remington introduced monoclonal IgG antibodies that specifically detect transferrin (Page 1, [0019]) and noted the need for a faster and more accurate detection system for cerebrospinal fluid leakage (Page 1, [0004]). A skilled artisan would have been motivated to combine the above methods to achieve the specificity of detecting cerebrospinal fluid leakage without any interference. It would have been obvious for a PHOSITA to use the monoclonal antibodies of Remington in the combined methods of Kelly, Gornik and Palmer to achieve a better differential diagnosis and detection of cerebrospinal fluid leakage. A PHOSITA would have had a reasonable expectation of success in combining the methods of Remington, Kelly, Gornik and Palmer based on the methods being in the field of detecting a target antigen in body fluids by immunoassays.
Response to Arguments
Applicant’s amendments of claim 1 and arguments, see page 8 of Applicant’s remarks, filed 06/26/2026, with respect to the rejections of claims 1-15 under 35 U.S.C. 103, regarding obviousness, have been fully considered and are persuasive. Therefore, the rejections have been withdrawn. However, upon further consideration, a new ground of rejection is made in view of newly found prior art reference of Kelly et al (Nature Nanotechnology, Vol 10, May 2015, pages 472-479) and in combination with Palmer et al. (US 2014/0004622 A1) and Gornik et al. (Clinical Biochemistry, 40 (2007), 718–723).
Conclusion
No claims are allowed.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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