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.
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
Claims 1-15 are part of the claim set of 11/26/2024 that was not amended by the Applicant.
Claims 16-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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.
Thus, claims 1-15 are under examination.
Maintained 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) and Gornik et al. (Clinical Biochemistry, 40 (2007), 718–723).
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 can 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 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 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 what Gornik taught over Palmer to improve the detection of cerebrospinal fluid leakage in a sample by using asialo-transferrin. A skilled artisan would have been motivated to make and use the claimed methods because Gornik taught a method on how to improve the detection of transferrin-specific antibodies by oxidizing their glycan part (Page 720, right column, second and third paragraph). 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 (Page 720, right column, second paragraph). Palmer showed that unlike beta-1 transferrin which is the major transferrin in serum, beta-2 transferrin is the major transferrin in cerebrospinal fluid that is believed to be without sialic acid residues. Thus, a sialic acid-specific lectin can be used to deplete the sample of the serum transferrin or beta-1 transferrin before using an antibody to detect beta-2 transferrin as was shown by Palmer. A skilled artisan would have been motivated to combine the two methods to produce a method that can specifically detect a marker of cerebrospinal leakage. It would have been obvious for a PHOSITA to use the antibody oxidation method of Gornik in the 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
Gornik and Palmer based on both being methods in the field of detecting a target antigen in body fluids by immunoassays.
Regarding claim 1, Palmer teaches using a separation section and a lateral flow immunoassay section (Page 3, [0028]; 12, claim 28). Palmer teaches that the sample can be introduced to the separation section before being transferred to a sample pad on the lateral flow immunoassay section (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”). While Palmer does not state centrifuging the sample before transferring the sample to the lateral flow immunoassay, Palmer stated that lectin-depletion of beta-1 transferrin can be performed in a tube. A skilled artisan would have been able to perform depletion of transferrin-1 in a test tube and follow up with centrifugation to separate lectin-bound fraction from non-bound fraction because centrifugation has been long and commonly practiced technique to concentrate and separate desired materials. The non-bound or lectin-depleted fraction can be further bound to conjugated antibodies to any transferrin as shown by Palmer (Page 5, [0048]; page 11, claim 1).
Claims 2 and 7 are rejected 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) as applied to claim 1 above, and further in view of Remington et al. (US 2004/0002168 A1).
Regarding claims 2 and 7, Palmer and Gornik teaches all of the limitations of claim 1 above, but Palmer fails to teach the following.
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 what Remington taught over Palmer to improve the detection of cerebrospinal fluid leakage in a sample by using asialo-transferrin. A skilled artisan would have been motivated to make and use the claimed methods because Remington introduced monoclonal IgG antibodies that can specifically detect transferrin (Page 1, [0019]). Remington noted the need for a faster and more accurate detection system for cerebrospinal fluid leakage (Page 1, [0004]). Palmer introduced a method for the rapid detection of cerebrospinal leakage by depleting interfering substances from the sample such as beta-1 transferrin (Page 2, [0019]). Palmer noted the need for a rapid, sensitive and cost-effective diagnostic test for cerebrospinal leakage (Page 1, [0004]). A skilled artisan would have been motivated to combine the above methods to achieve the specificity of detecting cerebrospinal leakage without any interference. It would have been obvious for a PHOSITA to use the monoclonal antibodies of Remington in the 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 Palmer and Remington based on both being methods in the field of detecting a target antigen in body fluids by immunoassays.
Response to Arguments
Applicant's arguments filed 11/24/2025 have been fully considered but they are not persuasive.
The Applicant alleged that the Office action of 08/25/2025 maintains that the method disclosed in Palmer removes all sialoglycoproteins, including beta-1 transferrin, from the physiological sample by the formation of immobilized lectin-sialo-glycoprotein conjugates on the sample pad. The Applicant further alleged that the Office action of 08/25/2025 asserts that this acts as, or obviates the necessity of, a pretreatment step, such as disclosed in the subject application.
This argument is not persuasive because the Office action of 08/25/2025 did not cite Palmer teaching against a pretreatment step. Palmer does provide such a suggestion which is clearly stated (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.”). Thus, Palmer clearly offers the option of a pretreatment step as taught in the instant application.
The Applicant alleged that in Palmer, gold nanoparticles act only to allow for the detection of beta-2 transferrin. The Applicant further alleged that centrifugation process in Palmer is the final step in producing the nanoparticle-antibody conjugates, rather than removing potentially confounding components from the physiological sample.
This argument is not persuasive because the language of claim 1 does not differentiate between the two forms of transferrin (i.e., beta-1 and beta-2 transferrin) when binding to nanoparticles. Furthermore, Palmer teaches using a separation section and a lateral flow immunoassay section (Page 3, [0028]; 12, claim 28). Palmer teaches that the sample can be introduced to the separation section before being transferred to a sample pad on the lateral flow immunoassay section (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”). While Palmer does not state centrifuging the sample before transferring the sample to the lateral flow immunoassay, Palmer stated that lectin-depletion of beta-1 transferrin can be performed in a tube. A skilled artisan would have been able to perform depletion of transferrin-1 in a test tube and follow up with centrifugation to separate lectin-bound fraction from non-bound fraction because centrifugation has been long and commonly practiced technique to concentrate and separate desired materials. The non-bound or lectin-depleted fraction can be further bound to antibodies to transferrin as shown by Palmer (page 11, claim 1).
The Applicant alleged that the Office action and Palmer fail to take into account two additional factors that influence the accuracy of the lateral flow test that are addressed in the subject application. The Applicant alleged that both factors relate to the fact that the pretreatment disclosed in the subject application guarantees that exclusively nanoparticle-conjugated transferrin (beta-1 or beta-2) is applied to the sample pad, removing any potential for unconjugated transferrin to interact with subsequent binding zones on the lateral flow device that may saturate their respective binding zones.
This argument is not persuasive because Palmer taught performing a pre-treatment step as discussed above. Briefly, Palmer clearly stated that 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 (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.”). Thus, Palmer clearly offers the option of a pretreatment step as taught in the instant application.
The Applicant alleged that dilution does not solve the problem of an extraneous species potentially binding to the membrane-immobilized antibodies independently of the conjugate complex, as binding would occur regardless of their concentration. The Applicant alleged that this extraneous species could bind to a degree where it influences the test result.
This argument is not persuasive because it defies the very basic operational concept of antigen antibody interaction. And it is not clear from Applicant’s arguments why diluting a sample with high concentration of an extraneous species would not minimize the interference effects. Mathematically and biochemically speaking, dilution leads to lowering the concentration of interferants in the sample used in the assay and thus less interferants to affect the antibody. Furthermore, Palmer stated that to prevent the “hook effect” from occurring, the sample can be diluted in a buffer prior to testing with a dilution factor of about 1 to 1600 to produce an optimal positive signal for beta-1 transferrin and no signal in the presence of sialic acid-specific Lectin gel such as Sambucus nigra lectin gel (SNA-gel) (Page 4, [0041]). Thus, a skilled artisan would have understood that there will be a need to optimize the dilution and depletion to obtain an optimal result of depleting beta-1 transferrin as stated above.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 OMAR RAMADAN whose telephone number is (571)270-0754. The examiner can normally be reached Monday-Friday 8:30 am - 5:00 pm.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678