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 .
Detailed Action
The Amendments and Remarks filed 8/14/26 in response to the Office Action of 5/15/26 are acknowledged and have been entered.
Claims 1-17 and 19-21 are pending.
Claims 1 and 3 have been amended by Applicant.
Claims 1-17 and 19-21 are currently under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Objections Withdrawn
Objection of claim 3 is withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claims 1, 2, 7, 10-16, and 19-21 are rejected under 35 U.S.C. 103(a) as being unpatentable over Jacobino et al (JACI, 2016, 138(5): 1477-1480) in view of Bangera et al (US 2015/0057505 A1; 2/26/15; 12/21/23 IDS).
Jacobino et al teaches amniotic fluid contains maternal antibodies and is in direct contact with the respiratory tract of a fetus (right column on page 1477, in particular). Jacobino et al further teaches IgG neutralizing antibodies against respiratory syncytial virus (RSV) can be present in amniotic fluid (Fig. 1) where they can contact the respiratory tract of a fetus and, using a mouse model, demonstrates these antibodies protect against RSV infection (Fig. 2). Jacobino et al further teaches concentrations of RSV neutralizing antibodies in amniotic fluid ranging from 0 to over 10 mg/mL, with most amniotic fluid having concentrations of the RSV neutralizing antibodies at 1-9 mg/mL (Figure 1D, in particular). Noting a high incidence of RSV infection during early childhood and that RSV infection in the first weeks of life is uncommon, Jacobino et al indicates newborns are likely to be protected against RSV infection from maternal RSV-neutralizing antibodies that are able to be delivered to the fetus within amniotic fluid (right column on page 1477 and right column on page 1479, in particular).
Jacobino et al does not specifically teach a method comprising administering an antibody to a fetus. However, these deficiencies are made up in the teachings of Bangera et al.
Bangera et al teaches methods of delivering a medicament, including a medicament that is a large molecule such as a protein, to a fetus by administering the medicament using microneedles to inject the medicament across an amniotic membrane to amniotic fluid of the fetus ([0066], in particular). Bangera et al further teaches volumes of amniotic fluid to range from 25-800 mL and that a 28 week fetus has an amniotic fluid volume of 800 mL (Example 1, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of reducing perinatal RSV infection by using the method of Banger et al to deliver human RSV IgG neutralizing antibodies as a medicament to the amniotic fluid of human fetuses that lack RSV neutralizing antibodies because the teachings of Jacobino et al indicate newborns are likely to be protected against RSV infection from human IgG RSV-neutralizing antibodies that are able to be delivered to the fetus within amniotic fluid (right column on page 1477 and right column on page 1479, in particular), Jacobino et al teaches that amniotic fluid of some fetuses lack maternal RSV-neutralizing antibodies (Figure 1, in particular), one of skill in the art would recognize antibodies are proteins, and method of Banger et al is taught to deliver proteins to a fetus by administering the proteins using microneedles to inject the proteins across an amniotic membrane to amniotic fluid of the fetus ([0066], in particular ). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention See MPEP 2143.
Further one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform said combined method wherein the antibody is administered at a dose to arrive at concentrations of the antibody in subjects with maternal antibody of about 25 mg to 7.2 mg because Jacobino et al teaches maternal RSV-neutralizing antibodies that provide therapeutic benefit are found in amniotic fluid at concentrations ranging from 1-9 mg/mL (Figure 1D, in particular) and Bangera et al further teaches volumes of amniotic fluid to range from 25-800 mL and that a 28 week fetus has an amniotic fluid volume of 800 mL (Example 1, in particular). 1 mg/mL x 25 mL = 25 mg. 9 mg/mL x 800 mL = 7.2 mg.
Further one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform said combined method during the last week of pregnancy because Jacobino et al teaches amniotic antibodies are sufficient to prevent virus infection for at least one week (right column on page 1479, in particular).
Further, the combined method would result in administered antibodies being in nasal tissue and serum with a reasonable expectation of success because Jacobino et al teaches antibodies in amniotic fluid are in contact with the respiratory tract of the fetus (right column on page 1477), where they can be taken-in by the fetus and be delivered through nasal tissue to serum.
In particular regards to claim 21, reagents of a method are a “kit”. Further, generating a “kit” for a given method provides two services: 1) a variety of different reagents have been assembled and pre-mixed specifically for a defined set of experiments. Thus, one need not purchase gram quantities of numerous different reagents when each of which may be needed in only microgram amounts, when beginning a series of experiments. When one considers all of the unused chemicals that typically accumulate in weighing rooms, desiccators, and freezers, one quickly realizes that it is actually far more expensive for a small number of users to prepare most buffer solutions from the basic reagents. In actuality, a kit format saves money and resources for everyone by dramatically reducing waste. 2) The other service provided in a kit is quality control. Therefore, it would have been prima facie obvious to one having ordinary skill in the art to combine the reagents of a method into a kit format since a kit provides a quality control, saves money, and saves resources.
Even if it is not clear from the prior art that administered antibodies of the combined method are “associated with the presence of and/or an increase in levels of the antibody in the serum of the fetus”, the claimed method remains non-obvious. This is because an association of the presence of or an increase in levels of the antibody in the serum of the fetus is not a property having a significance greater than that of the expected property of a predicted therapeutic effect of reducing perinatal RSV infection taught by the cited references. Therefore, recitation that administered antibodies have the property of being able to be associated with the presence of and/or an increase in levels of the antibody in the serum of the fetus is not sufficient to rebut obviousness of the combined method when the combined method is expected to have the equal or greater property of expected therapeutic benefit of reducing perinatal RSV infection. See MPEP 716.02(c). Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art. Further, see In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991), where the court held that the fact that another advantage would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 8/14/26, Applicant argues the Office Action of 5/15/26 incorrectly states “Jacobino et al teaches antibodies in amniotic fluid are in contact with the respiratory tract of the fetus (right column on page 1477), where they can be taken-in by the fetus and delivered through nasal tissue to serum.” Applicant further cites Ozsoy et al (Moelcules, 2009, 14(9): 3754-3779) and argues cited references are silent as to antibodies entering fetal serum through the respiratory tract and such a result would be a surprising result that is against knowledge in the art because nasal tissue is protected by a nasal epithelial barrier that is well known to be effectively impermeable to large molecules such as antibodies. Applicant further cites Jacobino as stating “[i]n humans, it is impossible to distinguish between the protective effects of maternal antibodies acquired into the respiratory mucosa via serum and [amniotic fluid]” and suggests the statement by Jacobino indicates serum and amniotic fluid are considered by Jacobino to be two completely separate sources of antibodies and if Jacobino expected amniotic fluid and serum to be connected this distinction would be meaningless.
The amendments to the claims and the arguments found in the Reply of 8/14/26 have been carefully considered, but are not deemed persuasive. In regards to the argument the Office Action of 5/15/26 incorrectly states “Jacobino et al teaches antibodies in amniotic fluid are in contact with the respiratory tract of the fetus (right column on page 1477), where they can be taken-in by the fetus and delivered through nasal tissue to serum”, the second to last sentence of the first full paragraph on the right column on page 1477 of Jacobino et al teaches “Amniotic fluid (AF) contains maternal antibodies and is in direct contact with the respiratory tract of the feus.” The examiner maintains that such antibodies in amniotic fluid in contact with the respiratory tract of the fetus can be taken-in by the fetus and delivered through nasal tissue to serum.
In regards to the citation of Ozsoy et al (Moelcules, 2009, 14(9): 3754-3779) and argument cited references are silent as to antibodies entering fetal serum through the respiratory tract and such a result would be a surprising result that is against knowledge in the art because nasal tissue is protected by a nasal epithelial barrier that is well known to be effectively impermeable to large molecules such as antibodies, Ozsoy et al does not teach the nasal epithelial barrier is impermeable to antibodies or would prevent antibodies in amniotic fluid from entering serum of a fetus.
In regards to the citation of Jacobino as stating “[i]n humans, it is impossible to distinguish between the protective effects of maternal antibodies acquired into the respiratory mucosa via serum and [amniotic fluid]” and suggestion the statement by Jacobino indicates serum and amniotic fluid are considered by Jacobino to be two completely separate sources of antibodies and if Jacobino expected amniotic fluid and serum to be connected this distinction would be meaningless, the examiner disagrees. Such a statement, indicating maternal antibodies can be acquired into the respiratory mucosa via both serum and amniotic fluid indicates the respiratory mucosa links amniotic fluid to serum and that antibodies in the respiratory mucosa could have arrived from amniotic fluid or serum.
Even if it is not clear from the prior art that administered antibodies of the combined method are “associated with the presence of and/or an increase in levels of the antibody in the serum of the fetus”, the claimed method remains obvious. This is because an association of the presence of or an increase in levels of the antibody in the serum of the fetus is not a property having a significance greater than that of the expected property of a predicted therapeutic benefit (including a therapeutic effect of reducing perinatal RSV infection taught by the cited references). Therefore, recitation that administered antibodies have the property of being able to be associated with the presence of and/or an increase in levels of the antibody in the serum of the fetus is not sufficient to rebut obviousness of a combined method when the combined method is expected to have the equal or greater property of expected therapeutic benefit (including a therapeutic effect of reducing perinatal RSV infection taught by the cited references). See MPEP 716.02(c). Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art. Further, see In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991), where the court held that the fact that another advantage would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.
Claim Rejections - 35 USC § 103
Claim(s) 1, 2, 7, 10-17, and 19-21 remain rejected under 35 U.S.C. 103 as being unpatentable over Jacobino et al (JACI, 2016, 138(5): 1477-1480) in view of Bangera et al (US 2015/0057505 A1; 2/26/15) as applied to claims 1, 2, 7, 10-15, and 19-21 above, and further in view of Dall’Acqua et al (JBC, 2006, 281(33): 23514-23514).
Response to Arguments
In the Reply of 8/14/26, Applicant repeats arguments addressed above.
Claim Rejections - 35 USC § 103
Claims 1-3, 5-7, 10, 13-16, and 19-21 remain rejected under 35 U.S.C. 103(a) as being unpatentable over Jacobino et al (JACI, 2016, 138(5): 1477-1480) in view of Workman et al (Journal of Hospital Infection, 1997, 35: 169-174), Nelson et al (JCI Insight, 2017, 2(13)(e94002: 1-18), Patel et al (BMJ, 2020, 105: F259-F265), and Bangera et al (US 2015/0057505 A1; 2/26/15).
Response to Arguments
In the Reply of 8/14/26, Applicant repeats arguments addressed above.
Claim Rejections - 35 USC § 103
Claims 1, 2, 4-7, 10, 13-16, and 19-21 are rejected under 35 U.S.C. 103(a) as being unpatentable over Jacobino et al (JACI, 2016, 138(5): 1477-1480) in view of Tiller et al (JOGNN, Jan/Feb 2002, 31(1): 93-98), Caldwell (Infection and Immunity, 1982, 38(2): 745-754), Ahmadi et al (BMC Pregnancy and Childbirth, 2018, 18(240): 1-7), and Bangera et al (US 2015/0057505 A1; 2/26/15).
Response to Arguments
In the Reply of 8/14/26, Applicant repeats arguments addressed above.
Claim Rejections - 35 USC § 103
Claims 8-9 remain rejected under 35 U.S.C. 103(a) as being unpatentable over Hartwell (AM J Clin Pathol, 1998, 110: 281-292) in view of Doran et al (Obstet Gynecol, 1983, 61(6): 737-742) and Bangera et al (US 2015/0057505 A1; 2/26/15).
Hartwell teaches a method for treating hemolytic disease of the fetus and newborn (HDN), which is a condition resulting from destruction of an Rh-positive infant’s red blood cells (RBCs) by IgG alloantibody produced by an Rh-negative mother, by administering to the pregnant mother RhIG antibody (pages 281 and 283, in particular). Hartwell further teaches it is believed RhIG antibody functions by attaching to D antigen sites on Rh-positive RBC and interfering with host primary immune response to foreign antigens (right column on page 282, in particular). Hartwell further teaches implications of a large fetomaternal hemorrhage occurring in an Rh-negative woman are “obvious” and that tests for fetomaternal hemorrhage are designed to detect fetal RBCs in the circulation of Rh-negative people (page 288, in particular).
Hartwell does not specifically teach administering RhIG antibody to amniotic fluid. However, these deficiencies are made up in the teachings of Doran et al and Bangera et al.
Doran et al teaches RBCs in amniotic fluid is usually considered undesirable and RBCs, likely of fetal origin, are sometimes found in amniotic fluid (Abstract, in particular).
Bangera et al teaches methods of delivering a medicament, including a medicament that is a large molecule such as a protein, to a fetus by administering the medicament using microneedles to inject the medicament across an amniotic membrane to amniotic fluid of the fetus ([0066], in particular). Bangera et al further teaches volumes of amniotic fluid to range from 25-800 mL and that a 28 week fetus has an amniotic fluid volume of 800 mL (Example 1, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating HDN in Rh-negative pregnant women with RBCs in amniotic fluid by both administering the RhIG antibody of Hartwell to the women and using the method of Banger et al to deliver the antibodies of Hartwell to Rh-positive RBC in the amniotic fluid of the women in order to interfere with host primary immune response to foreign antigens found in amniotic fluid (which can enter maternal blood stream upon fetomaternal hemorrhage, as taught by Hartwell) because the RhIG antibody of Hartwell functions by binding D antigen cites on RBCs of fetal origin, Doran et al teaches RBCs that are likely of fetal origin are found in amniotic fluid (again, which can enter maternal blood stream upon fetomaternal hemorrhage), and the method of Banger et al is taught to deliver proteins to a fetus by administering the proteins using microneedles to inject the proteins across an amniotic membrane to amniotic fluid of the fetus ([0066], in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 8/14/26, Applicant argues it is incorrect that a person of ordinary skill in the art would have been motivated to deliver RhIG antibodies to amniotic fluid of women in order to interfere with host primary immune response to foreign antigens found in amniotic fluid because amniotic fluid is not part of the maternal circulation system and RBCs in amniotic fluid would not cause Rh immunization and the person of ordinary skill in the art would not have been motivated to administer RhIG antibodies to the amniotic fluid. Applicant further argues administering IgG antibodies to the fetus that are reactive to the fetus’s RBC is counterproductive.
The arguments found in the Reply of 8/14/26 have been carefully considered, but are not deemed persuasive. In response to Applicant’s arguments, it would be obvious to perform the combined method for the reasons stated above. Further, it is well-known that fetal cells can enter the maternal circulation system upon fetomaternal hemorrhage (see right column on page 281 of Hartwell) and treating such cells in amniotic fluid prior to fetomaternal hemorrhage with RhIG antibodies of the combined method would predictably interfere with host primary immune response (Rh immunization) with such cells.
Conclusion
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 SEAN E AEDER whose telephone number is (571)272-8787. The examiner can normally be reached M-F 9am-6pm 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, Samira Jean-Louis can be reached at (571)270-3503. 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.
/SEAN E AEDER/Primary Examiner, Art Unit 1642
Prosecution Insights