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 .
Notice of New Examiner
The Examiner would like to note for the Applicant that this case has been
transferred to a new examiner for continued examination. Any further communications on this case may be directed to the contact information included in the conclusion of this
office action.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-10, 25-26, and 28-29 in the reply filed on April 10th, 2026 is acknowledged.
Claim 24 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 April 10th, 2026.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on February 13th, 2024 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Summary
Claims 1-10 and 24 have been amended. Claims 11-23 and 27 have been canceled. Claims 28 and 29 have been added. Claims 1-20, 24-26, and 28-29 are pending. Claim 24 is withdrawn from consideration as being drawn to a non-elected invention/species. Claims 1-10, 25-26, and 28-29 are under examination and discussed in this Office action.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see pages 37, 56, and 58). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use terms such as TRANSFAC, which is a trade name or a mark used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-10, 25-26, and 28-29 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 1 recites the limitation “[a] method of detecting a cell free DNA chromatin fragment including all or a part of a transcription factor binding site sequence in a body fluid sample obtained from a human or animal subject, comprising: (i) contacting the body fluid sample with a binding agent which binds to a nucleosome; and (ii) analyzing the DNA from the body fluid sample not bound to the binding agent in step (i).” It is unclear from this recitation how only the DNA not bound to the binding agent is analyzed when there is not a recited separation or isolation step that either removes the nucleosomes bound to the binding agent or separates out the DNA not bound to the binding agent. Depending on the analysis method chosen, all DNA present will be analyzed. For instance, if the analysis method is sequencing, without removal of the nucleosomes bound to the binding agent and therefore removing the non-target DNA, all DNA will be sequenced. This same issue is noted for claim 2 and claim 25, both of which claim similar methods.
Claim 1 also recites the limitation " the DNA " in line 7 of the claim. There is insufficient antecedent basis for this limitation in the claim. The claim earlier introduces “cell free DNA”, not “DNA”. The same issue is noted for claim 2, which claims a similar method.
Claims 3-10, 26, and 28-29 are also rejected here for their dependence on claims 1, 2, or 25 and not further clarifying the identified issue. For the purpose of compact prosecution, it will be interpreted that there is a step of separating the bound DNA from the unbound DNA.
Claim 9 recites the limitation “wherein the DNA is analyzed by PCR”. There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 9 depends, introduces “cell free DNA”, not “DNA”.
Claim 25 recites the limitation “A method of treating a disease in a subject in need thereof, wherein said method comprises the following steps: (i) contacting a body fluid sample obtained from the human or animal subject with a binding agent which binds to a nucleosome; (ii) detecting or measuring a DNA fragment not bound to the binding agent in step (i); (iii) using the presence, sequence, amount or fragmentation pattern of the DNA fragment as an indicator of the presence of the disease in the subject; and (iv) administering a treatment if the subject is determined to have the disease in step (iii).” It is unclear from this recitation how DNA fragments can be measured when there is no recited fragmentation step as a part of the method. There is also no indication in the claim that the DNA measured is naturally occurring fragmented DNA, such as cell free DNA which circulates in body fluid samples as fragments (see page 1 of the instant specification), to indicate that a fragmentation step is not required. Therefore, the claim is found indefinite. Claim 26 is also rejected here for its dependence on claim 25 and not further clarifying the identified issue. For the purpose of compact prosecution, given the inclusion of other claims and description in the specification directed towards cell free DNA, the DNA fragments of claim 25 will be interpreted as cell free DNA.
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 10 and 25-26 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to a natural phenomenon without significantly more. While the claims are directed to processes, and therefore meet step 1 of the subject matter eligibility test (see MPEP 2106.03), the claims all recite the natural correlation between the features of cfDNA and disease. Such correlation is a natural phenomenon because it describes a consequence of natural processes in the human body.
Step 2A of the subject matter eligibility test requires a two-pronged analysis. Prong One asks: does the claim recite an abstract idea, law of nature or natural phenomenon? As discussed in MPEP 2106.04(II)(A)(1), the meaning of “recites” is “set forth” or “describes”. That is, a claim recites a judicial exception when the judicial exception is “set forth” or “described” in the claim. In the instant case, the claims describe a natural phenomenon: the natural correlation between features of cfDNA and disease.
Prong Two of the analysis under step 2A asks: does the claim recite additional elements that integrate the judicial exception into a practical application of the judicial exception? As discussed in MPEP 2106.04(II)(A)(2), “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B.” The considerations to be used are set forth at MPEP 2106.05(a) through (c) and (e) through (h). Turning to those sections of the MPEP:
MPEP 2106.05(a) has to do with improvements to the functioning of a computer or to any other technology or technical field. The claims at issue do not improve the functioning of a computer or other technology. The instant claims recite two different methods, the first of which comprising the steps: detecting a cell free DNA chromatin fragment including all or part of a transcription factor binding site sequence in a body fluid sample obtained from a human or animal subject, comprising: (i) contacting the body fluid sample with a binding agent which binds to a nucleosome; and (ii) analyzing the DNA from the body fluid sample not bound to the binding agent in step (i); and determining a presence, amount, sequence or fragmentation pattern of the DNA as an indicator of the disease state of the subject. The second method comprises the steps (i) contacting a body fluid sample obtained from the human or animal subject with a binding agent which binds to a nucleosome; (ii) detecting or measuring a DNA fragment not bound to the binding agent in step (i); (iii) using the presence, sequence, amount or fragmentation pattern of the DNA fragment as an indicator of the presence of the disease in the subject; and (iv) administering a treatment if the subject is determined to have the disease in step (iii); wherein the treatment administered is selected from: surgery, radiotherapy, chemotherapy, immunotherapy, hormone therapy and biological therapy. However, the claims do not improve upon binding assays, DNA analysis, or determining disease. The claims merely use existing methods for these steps. Note that MPEP 2106.05(a) indicates that “[u]sing well-known standard laboratory techniques to detect enzyme levels in a bodily sample” is an example that the courts have indicated may not be sufficient to show an improvement to technology.
MPEP 2106.05(b) has to do with whether the claims involve the use of a particular machine. In this case, the claims do not involve the use of a particular machine. While the instant claims in question recite methods as detailed above, no such machines are required by the claim, and certainly no particular machines. Even if some conventional machine were recited in the claims, like a particular PCR device, further considerations such as the particularity or generality of the recited machine must be taken into account, as well as whether the involvement of the machine is merely extra-solution activity. MPEP 2106.05(g) describes “extra-solution activity”, noting that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra-solution activity.
MPEP 2106.05(c) has to do with whether the claims involve a particular transformation. Here, none of the limitations of the claims involve a particular transformation. For example, analyzing cfDNA does not transform that cfDNA into something else.
MPEP 2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the natural correlation between features of cfDNA and disease in the instant case have to do with contacting the body fluid sample with a binding agent which binds to a nucleosome and analyzing the DNA from the body fluid sample not bound to the binding agent, as well as generic treatment steps. These limitations are not considered “meaningful limitations”. MPEP 2106.05(e) states: “The phrase "meaningful limitations" has been used by the courts even before Alice and Mayo in various contexts to describe additional elements that provide an inventive concept to the claim as a whole.” In addition, as has been discussed, they represent insignificant extra-solution activity, i.e. “data gathering”.
MPEP 2106.05(f) raises the question as to whether the additional elements recited in the claim represent “mere instructions to apply an exception”. Here, the judicial exception is the natural correlation between features of cfDNA and disease. The additional elements recited in the claims (i.e. contacting the body fluid sample with a binding agent which binds to a nucleosome and analyzing the DNA from the body fluid sample not bound to the binding agent, as well as generic treatment steps) does amount to mere instructions to apply the correlation, since the these methods serve as mere conventional steps taken for the purpose of gathering data about the cfDNA features in a subject, which any practical use of the natural correlation would require.
MPEP 2106.05(g) has to do with whether the additional elements of the claim amount to insignificant extra-solution activity. MPEP 2106.05(g) notes that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra - solution activity. Likewise, MPEP 2106.05(g) notes that “[p]erforming clinical tests on individuals to obtain input for an equation” also represents insignificant extra-solution activity. This aligns closely with the instant claims, where the additional elements of the claims amount to gathering samples, contacting with a binding agent, and analyzing DNA not bound to the binding agent.
MPEP 2106.05(h) has to do with whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. Here, the recitation of the field of the invention in the specification stating “a method for detecting disease in a subject by means of a minimally invasive blood test for transcription factor occupancy of cell free DNA fragments” (Page 1 of the instant specification) is considered a “field of use”. However, as MPEP 2106.05(h) indications, such limiting to a particular “field of use” does not confer patentability on otherwise ineligible subject matter.
In addition, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception (as set forth in step 2B of the subject matter eligibility test; see MPEP 2106-III) because it was routine and conventional in the prior art to analyze cfDNA from a body sample as it relates to disease, as well as contact the sample with a binding agent, examine DNA not bound to the binding agent, and administer a generic treatment based on the relation to disease.
For example, Garofalo (Deep Sequencing of Viral Cell-Free DNA for Noninvasive Detection of Immunosuppression-Related Lymphoid Malignancies, Blood, November 2019, 134, 1-4) teaches on analyzing DNA from a body fluid sample obtained from a human by sequencing of viral cell free DNA (cfDNA) of viruses related to viral-driven lymphoma from plasma samples (whole document). Garofalo teaches on a method of detecting a viral cell free DNA chromatin fragmentation pattern in a body fluid sample obtained from a human (whole document). Garofalo does not directly teach on detecting specifically transcription factor binding sites or viral cfDNA comprising chromatin fragments. However, as indicated in in the results section of Garofalo, the virus panel is designed to capture a median of 95.9% of targeted virus. This would necessarily include transcription factor binding sites. As evidenced by Tierney (Methylation of Transcription Factor Binding Sites in the Epstein-Barr Virus Latent Cycle Promoter Wp Coincides with Promoter Down-Regulation during Virus-Induced B-Cell Transformation, Journal of Virology, November 2000, 74, 10468-10479), viruses like Epstein-Barr Virus have transcription factor binding sites (whole document). Furthermore, with regard to viral DNA chromatin, as evidenced by Lieberman (Chromatin regulation of virus infection, Trends in Microbiology, March 2006, 14, 132-140), viral DNA may be formed into chromatin like structures (Page 132, column 2, paragraph 2). Therefore, the virus cfDNA of Garofalo would necessarily include chromatin fragments. Garofalo further teaches the method further comprising determining a presence of the DNA as an indicator of the disease state of the subject (Page 2, Background). Garofalo teaches a method of treating a disease in a subject in need thereof, wherein said method comprises the following steps: (iii) using the presence of a viral cfDNA fragment as an indicator of the presence of the disease in the subject (whole document). Garofalo does not directly teach on administering a treatment if the subject is determined to have the disease in step (iii). However, Garofalo suggests that their method of detection for viral cfDNA “holds promise for monitoring diverse features of viral cfDNA that capture risks for malignancy and immunosuppression, facilitating personalized diagnostic and therapeutic interventions” (Page 3, Conclusions).
Stone (US 20080131954 A1) teaches contacting the body fluid sample with a binding agent which binds to a nucleosome and separating non-target DNA bound to the nucleosome from target DNA (Page 1, paragraph [0012]). Stone further teaches removal of non-target DNA removes background DNA prior to the amplification and detection steps of diagnostic procedures (Page 3, paragraph [0031]; Page 4, paragraph [0038]). Stone teaches further specific details about the binding agent (Pages 2-3, paragraph [0025]). Stone teaches wherein the binding agent is attached to a solid support (Page 3, paragraph [0027]).
Eccleston (US 20190064184 A1) teaches on histone H1 binding agents which bind to the histone H1 protein (Page 6, paragraph [0097]) that may be used to isolate nucleosomes containing histone H1 (Page 5, paragraph [0069]). Eccleston teaches on treatment options for cancer including chemotherapy (Page 11, paragraph [0226]).
Kimura (Monitoring of cell-free viral DNA in primary Epstein-Barr virus infection, Medical Microbiology and Immunology, June 2000, 188, 197-202) teaches viral cfDNA can be analyzed by a PCR method (Page 197, column 2, paragraph 2 to Page 198, column 1, paragraph 1; Page 198, column 2, paragraph 2).
Therefore, the additional elements beyond the natural correlation between features of cfDNA and disease do not represent an inventive concept since analyzing cfDNA from a body sample as it relates to disease, as well as contacting the sample with a binding agent and examining DNA not bound to the binding agent, and administering a generic treatment based on the relation to disease, was routine, well-known and conventional.
Having considered the factors discussed in MPEP 2106.04(c)(II) and MPEP 2106.05 (a)-(c) and (e)-(h), as well as the prior art of Garofalo, Stone, Eccleston, and Kimura, it is clear that the additional elements recited in the claims, whether considered individually or as a combination, do not integrate the judicial exception into a practical application of that exception in such a way as to provide meaningful limits on the use of the judicial exception. Therefore, claims 10 and 25-26 are rejected here under 35 U.S.C. 101.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5, 7-8, 10, 25, and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Garofalo (Deep Sequencing of Viral Cell-Free DNA for Noninvasive Detection of Immunosuppression-Related Lymphoid Malignancies, Blood, November 2019, 134, 1-4), in view of Stone (US 20080131954 A1), as evidenced by Tierney (Methylation of Transcription Factor Binding Sites in the Epstein-Barr Virus Latent Cycle Promoter Wp Coincides with Promoter Down-Regulation during Virus-Induced B-Cell Transformation, Journal of Virology, November 2000, 74, 10468-10479) and Lieberman (Chromatin regulation of virus infection, Trends in Microbiology, March 2006, 14, 132-140).
Regarding instant claim 1, Garofalo teaches on analyzing DNA from a body fluid sample obtained from a human by sequencing of viral cell free DNA (cfDNA) of viruses related to viral-driven lymphoma from plasma samples (whole document). Garofalo does not directly teach on detecting specifically transcription factor binding sites or viral cfDNA comprising chromatin fragments. However, as indicated in in the results section of Garofalo, the virus panel is designed to capture a median of 95.9% of targeted virus (Page 2, Results). This would necessarily include transcription factor binding sites. As evidenced by Tierney, viruses like Epstein-Barr Virus have transcription factor binding sites (whole document). Furthermore, with regard to viral DNA chromatin, as evidenced by Lieberman, viral DNA may be formed into chromatin like structures (Page 132, column 2, paragraph 2). Therefore, the virus cfDNA of Garofalo would necessarily include chromatin fragments.
Garofalo does not teach (i) contacting the body fluid sample with a binding agent which binds to a nucleosome; and (ii) analyzing the DNA from the body fluid sample not bound to the binding agent in step (i).
Stone, in a reasonably pertinent field, teaches contacting the body fluid sample with a binding agent which binds to a nucleosome and separating non-target DNA bound to the nucleosome from target DNA (Page 1, paragraph [0012]; see 112(b) interpretation). Stone further teaches removal of non-target DNA removes background DNA prior to the amplification and detection steps of diagnostic procedures (Page 3, paragraph [0031]; Page 4, paragraph [0038]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Garofalo with the separation method of Stone. Since Stone teaches on separation of host DNA from viral DNA, which is reasonably pertinent to the method of Garofalo, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because “[t]his methodology is beneficial due to its ease of use and can be adapted to commercial platforms that utilize DNA separation by magnets. The removal of chromatin from the cell lysate allows for the enrichment of bacterial, viral and/or fungal DNA over the background of host DNA” (Stone, Page 3, paragraph [0031]).
Regarding instant claim 2, Garofalo teaches on a method of detecting a viral cell free DNA chromatin fragmentation pattern in a body fluid sample obtained from a human (whole document). Garofalo does not directly teach on viral cfDNA comprising chromatin fragments. With regard to viral DNA chromatin, as evidenced by Lieberman, viral DNA may be formed into chromatin like structures (Page 132, column 2, paragraph 2). Therefore, the virus cfDNA of Garofalo would necessarily include chromatin fragments.
Garofalo does not teach (i) contacting the body fluid sample with a binding agent which binds to a nucleosome; and (ii) analyzing the DNA from the body fluid sample not bound to the binding agent in step (i).
Stone, in a reasonably pertinent field, teaches contacting the body fluid sample with a binding agent which binds to a nucleosome and separating non-target DNA bound to the nucleosome from target DNA (Page 1, paragraph [0012]; see 112(b) interpretation). Stone further teaches removal of non-target DNA removes background DNA prior to the amplification and detection steps of diagnostic procedures (Page 3, paragraph [0031]; Page 4, paragraph [0038]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Garofalo with the separation method of Stone. Since Stone teaches on separation of host DNA from viral DNA, which is reasonably pertinent to the method of Garofalo, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because “[t]his methodology is beneficial due to its ease of use and can be adapted to commercial platforms that utilize DNA separation by magnets. The removal of chromatin from the cell lysate allows for the enrichment of bacterial, viral and/or fungal DNA over the background of host DNA” (Stone, Page 3, paragraph [0031]).
Regarding instant claim 3, Garofalo, in view of Stone teaches the method of claim 1. Stone further teaches wherein the binding agent binds to a nucleosome core epitope (Pages 2-3, paragraph [0025]).
Regarding instant claim 4, Garofalo, in view of Stone, teaches the method of claim 1. Stone further teaches wherein the binding agent binds to a nucleosome containing linker DNA (Pages 2-3, paragraph [0025]).
Regarding instant claim 5, Garofalo, in view of Stone, teaches the method according to of claim 4. Stone further teaches wherein the binding agent is all or a part of a chromatin binding protein (Pages 2-3, paragraph [0025]).
Regarding instant claim 7, Garofalo, in view of Stone, teaches the method of claim 1. Stone further teaches wherein the binding agent is attached to a solid support (Page 3, paragraph [0027]).
Regarding instant claim 8, Garofalo, in view of Stone, teaches the method of claim 2. Garofalo does not directly teach on detecting specifically transcription factor binding sites. However, as indicated in in the results section of Garofalo, the virus panel is designed to capture a median of 95.9% of targeted virus (Page 2, Results). This would necessarily include transcription factor binding sites. As evidenced by Tierney, viruses like Epstein-Barr Virus have transcription factor binding sites (whole document).
Regarding instant claim 10, Garofalo, in view of Stone, teaches the method of claim 1. Garofalo further teaches the method further comprising determining a presence of the DNA as an indicator of the disease state of the subject (Page 2, Background).
Regarding instant claim 25, Garofalo teaches a method of treating a disease in a subject in need thereof, wherein said method comprises the following steps: (iii) using the presence of a viral cfDNA fragment as an indicator of the presence of the disease in the subject (whole document; see 112(b) interpretation). Garofalo does not directly teach on administering a treatment if the subject is determined to have the disease in step (iii). However, Garofalo suggests that their method of detection for viral cfDNA “holds promise for monitoring diverse features of viral cfDNA that capture risks for malignancy and immunosuppression, facilitating personalized diagnostic and therapeutic interventions” (Page 3, Conclusions). Therefore, it would be obvious to one of ordinary skill in the art that administering a treatment can be based on the method of Garofalo.
Garofalo does not teach (i) contacting a body fluid sample obtained from a human or animal subject with a binding agent which binds to a nucleosome; and (ii) detecting or measuring a DNA fragment not bound to the binding agent in step (i).
Stone, in a reasonably pertinent field, teaches contacting a body fluid sample with a binding agent which binds to a nucleosome and separating non-target DNA bound to the nucleosome from target DNA (Page 1, paragraph [0012]; see 112(b) interpretation). Stone further teaches removal of non-target DNA removes background DNA prior to the amplification and detection steps of diagnostic procedures (Page 3, paragraph [0031]; Page 4, paragraph [0038]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Garofalo with the separation method of Stone. Since Stone teaches on separation of host DNA from viral DNA, which is reasonably pertinent to the method of Garofalo, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because “[t]his methodology is beneficial due to its ease of use and can be adapted to commercial platforms that utilize DNA separation by magnets. The removal of chromatin from the cell lysate allows for the enrichment of bacterial, viral and/or fungal DNA over the background of host DNA” (Stone, Page 3, paragraph [0031]).
Regarding instant claim 28, Garofalo, in view of Stone, teaches the method of claim 2. Stone further teaches wherein said contacting comprises contacting the body fluid sample with a binding agent which binds to a nucleosome containing linker DNA (Pages 2-3, paragraph [0025]).
Regarding instant claim 29, Garofalo, in view of Stone, teaches the method of claim 3. Stone further teaches wherein the binding agent binds to histone H3 (Pages 2-3, paragraph [0025]).
Claims 6 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Garofalo (Deep Sequencing of Viral Cell-Free DNA for Noninvasive Detection of Immunosuppression-Related Lymphoid Malignancies, Blood, November 2019, 134, 1-4) and Stone (US 20080131954 A1), as applied to claims 1-5, 7-8, 10, 25, and 28-29, and further in view of Eccleston (US 20190064184 A1).
Regarding instant claim 6, Garofalo, in view of Stone, teaches the method according to of claim 4. Stone further teaches that the binding agent is an anti-histone antibody (Pages 2-3, paragraph [0025]).
Neither reference teaches wherein the binding agent binds to histone H1 or a component thereof.
Eccleston, in the same field of endeavor, teaches on histone H1 binding agents which bind to the histone H1 protein (Page 6, paragraph [0097]) that may be used to isolate nucleosomes containing histone H1 (Page 5, paragraph [0069]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Garofalo, in view of Stone, with the H1 histone binding agent of Eccleston. Since both Garofalo, in view of Stone, and Eccleston are in the same field of endeavor (e.g. isolating nucleosomes using binding agents), one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because it amounts to simple substitution of one known element for another (see MPEP 2141(III)).
Regarding instant claim 26, Garofalo, in view of Stone, teaches the method according to claim 25. Garofalo further teaches on their method being able to facilitate therapeutic interventions after monitoring for malignancy related to viral cfDNA (Page 3, Conclusions).
Neither reference teaches wherein the treatment administered is selected from: surgery, radiotherapy, chemotherapy, immunotherapy, hormone therapy and biological therapy.
Eccleston, in the same field of endeavor, teaches on treatment options for cancer including chemotherapy (Page 11, paragraph [0226]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Garofalo, in view of Stone, with the treatment option of Eccleston. Since both Eccleston and Garofalo, in view of Stone, are in the same field of endeavor (e.g. cfDNA related to cancer), one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because it amounts to simple substitution of one known element for another to obtain predictable results (see MPEP 2141(III)). The therapeutic interventions of Garofalo may be substituted for an appropriate intervention such as chemotherapy.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Garofalo (Deep Sequencing of Viral Cell-Free DNA for Noninvasive Detection of Immunosuppression-Related Lymphoid Malignancies, Blood, November 2019, 134, 1-4) and Stone (US 20080131954 A1), as applied to claims 1-5, 7-8, 10, 25, and 28-29, and further in view of Kimura (Monitoring of cell-free viral DNA in primary Epstein-Barr virus infection, Medical Microbiology and Immunology, June 2000, 188, 197-202).
Regarding instant claim 9, Garofalo, in view of Stone, teaches the method of claim 1. Garofalo teaches that viral cell free DNA is analyzed by sequencing (whole document).
Neither reference teaches wherein the DNA is analyzed by PCR.
Kimura, in a reasonably pertinent field, teaches viral cfDNA can be analyzed by a PCR method (Page 197, column 2, paragraph 2 to Page 198, column 1, paragraph 1; Page 198, column 2, paragraph 2).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Garofalo, in view of Stone, with the PCR method of Kimura. Since Kimura teaches on analysis of viral cfDNA, which is reasonably pertinent to the viral cfDNA analysis of Garofalo, in view of Stone, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because it amounts to simple substitution of one known element for another to obtain predictable results (see MPEP 2141(III)). The sequencing method of Garofalo and the PCR method of Kimura both serve to analyze viral cfDNA.
Conclusion
All claims stand rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allison E Schloop whose telephone number is (703)756-4597. The examiner can normally be reached Monday-Friday 8:30-5 ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at (571) 272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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