Merial Limited v Zoetis Services LLC

Case •

[2017] APO 20

•

5 May 2017

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Merial Limited v Zoetis Services LLC [2017] APO 20

Patent Application:                2007343130

Title:Methods of vaccine administration

Patent Applicant:                   Zoetis Services LLC

Opponent:  Merial Limited

Delegate:  Dr B. Akhurst

Decision Date:  5 May 2017

Hearing Date:  24 February 2017, in Canberra

Catchwords:  PATENTS – section 59 – final determination – amendments do not overcome the deficiencies identified in previous decision – further opportunity provided to amend.

Representation:  Counsel for the applicant:  Mr Patrick Flynn

Patent attorney for the applicant:  Dr Tony Shaw of Allens Patent and Trade Mark Attorneys

Counsel for the opponent:  Mr Jonathan Gottschall

Patent attorneys for the opponent: Dr Jenny Petering and Dr Karin Innes of FB Rice

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Patent Application:                2007343130

Title:Methods of vaccine administration

Patent Applicant:                   Zoetis Services LLC

Date of Decision:                   5 May 2017

DECISION

The amendments to the specification do not overcome the deficiencies identified in the earlier decision. 

Zoetis Services LLC has one month from the date of this decision to propose amendments to the claims.

I award costs according to Schedule 8 against Zoetis Services LLC.

REASONS FOR DECISION

Background

  1. Patent application 2007343130 was advertised as accepted on 20 December 2012 and is presently owned by Zoetis Services LLC (Zoetis).  After Merial Limited (Merial) opposed the grant of the patent, the matter was heard and on 7 March 2016 my decision that the opposition succeeded on the ground of inventive step was reported as [2016] APO 12 (the earlier decision).  However, I allowed Zoetis a period of time in which to propose amendments to the claims.

  2. Zoetis proposed amendments under s 104 (the amendments) which were allowed unopposed on 15 September 2016.  Merial requested to be heard before the s 59 opposition was finally determined and a hearing was held in Canberra on 24 February 2017.

    The law

  3. It is well established that the decision of the delegate in opposition proceedings is final, and determines all the issues arising on the notice of opposition so far as they are capable of determination at the time (R v Smith; Ex parte Mole Engineering Pty Ltd [1981] HCA 25; (1981) 147 CLR 340 at 348-349). In a final determination of an opposition the issues to be considered are whether the amendments overcome the deficiencies identified in the earlier decision, and whether the amendments introduce any new deficiencies.

    The amendments

  4. The amended claims consist of two independent claims and 17 dependent claims.  Independent claims 1 and 2 as amended are reproduced below:

    1. A method of treating a dog for canine diseases comprising administering to the dog therapeutically effective amounts of a vaccine;

    wherein the vaccine comprises viral antigens and a bacterin;

    wherein the viral antigens comprise 1) canine distemper (CD) virus, 2) canine adenovirus type 2 (CAV-2), 3) canine parainfluenza (CPI) virus, and 4) canine parvovirus (CPV);
    wherein the bacterin comprises one or more bacteria selected from Leptospira canicola, L. grippotyphosa, L. icterohaemorrhagiae, L. pomona, L. bratislava, and Bordetella bronchiseptica;
    wherein the vaccine is administered orally in a first dose, orally in a second dose, orally in a third dose, and orally in one or more annual doses;
    wherein the second dose is administered from 7 to 35 days, inclusive, after the first dose; and
    wherein the third dose is administered from 7 to 35 days, inclusive, after the second dose.

    2. A method of treating a dog for canine diseases comprising administering to the dog therapeutically effective amounts of a vaccine;
    wherein the vaccine comprises viral antigens and a bacterin;
    wherein the viral antigens comprise 1) canine distemper (CD) virus, 2) canine adenovirus type 2 (CAV-2), 3) canine parainfluenza (CPI) virus, and 4) canine parvovirus (CPV);
    wherein the bacterin comprises one or more bacteria selected from Leptospira canicola, L. grippotyphosa, L. icterohaemorrhagiae, L. pomona, L. bratislava, and Bordetella bronchiseptica;
    wherein the vaccine is administered subcutaneously in a first dose, orally or subcutaneously in a second dose, orally in a third dose, and orally in one or more annual doses;
    wherein the second dose is administered from 7 to 35 days, inclusive, after the first dose; and
    wherein the third dose is administered from 7 to 35 days, inclusive, after the second dose.

  5. The nature of the amendments to claims 1 and 2 can be summarised as follows:

    (i) the vaccine requires viral antigens and a bacterin rather than either one or both;

    (ii) the vaccine requires all four of the CD, CAV-2, CPI and CPV antigens, rather than any one or more of the CD, CAV-2, CPI, CPV and CCV antigens;

    (ii) claim 1 requires that the first dose be administered orally, rather than subcutaneously or orally;

    (iii) claim 2 allows for the second dose to be administered subcutaneously or orally, rather than  only subcutaneously;

    (iv) an oral third dose is required, rather than being optional; and

    (v) the second and third doses are required to be administered from 7 to 35 days, inclusive, after the first and second doses, respectively.

  6. The accepted claims (the subject of the earlier decision) and the amended claims in their entirety are attached to this decision as Annexes A and B, respectively.

  7. All of the features now present in amended claims 1 and 2 can be identified in the accepted claims.  Accepted claims 4-6 define combinations of the core canine antigens and bacterins, and accepted claims 15 and 17 define the dosing intervals of the second and third doses, respectively.  However, no one claim in the accepted claim set recites the specific combination of features now present in either one of amended claims 1 or 2.

  8. There was some discussion at the hearing as to what “therapeutically effective amount” means in the context of the amended claims.  Although not discussed in the earlier decision, “therapeutically effective amount” is defined at page 6 of the specification as:

    “an amount of an antigen or vaccine that would induce an immune response in a subject receiving the antigen or vaccine which is adequate to prevent signs or symptoms of disease, including adverse health effects or complications thereof, caused by infection with a pathogen, such as a virus or bacterium. … The amount of a vaccine that is therapeutically effective may vary depending on the particular virus used, or the condition of the subject, and can be determined by a veterinary physician.”

  9. Zoetis submitted that since the amended claims require the vaccine to include a combination of antigens and bacterins, the requirement in claims 1 and 2 for a therapeutically effective amount of vaccine means that the vaccine must be effective against all the diseases associated with the specified antigens and bacterins. Zoetis submitted that such a construction is consistent with the proper construction of claims to ‘a method for treating a dog for canine diseases’ and with the purpose of combination vaccines being the treatment (albeit prophylactically) of multiple diseases. In contrast, Merial submitted that the reference in claims 1 and 2 to “therapeutically effective amounts of a vaccine” was satisfied by one or more of the included antigens having a therapeutically beneficial effect. I identified principles to be applied in construing claims in the earlier decision at [22]. Having regard to the context of the specification, which exemplifies the ability of a combination vaccine to elicit seroconversion against multiple antigens, and the evidence of both declarants that existing combination vaccines provide protection against all the components of the combination (Bevan#1 at [6], [7]; Holloway#1 at [4(c)]), I am satisfied that it is sensible to adopt Zoetis’ construction.

    Inventive step

  10. The opposition was successful on the ground of inventive step in light of two documents, WO 2006/038115 (Pfizer Products, Inc.) 13 April 2006 (WO’115) and Baer, G.M. et al. (1989) American Journal of Veterinary Research 50(6): 836-837 (Baer).

  11. In the earlier decision at [79] I formulated the problem as “the provision of an alternative and more convenient administration regimen for canine vaccines”. 

    WO’115

  12. My finding in relation to WO’115 is summarised at paragraphs [119] and [120] of the earlier decision as follows:

    “I am satisfied that before the priority date, in all the circumstances (including knowledge of the problem and the disclosure of WO’115), the person skilled in the art or team would directly be led as a matter of course to try treating a dog for canine diseases by administering the core canine vaccine antigens or combinations of antigens identified in WO’115, in 2-3 doses followed by one or more annual boosters, all orally or in a combination of one or two subcutaneous doses followed by oral doses, with a reasonable expectation that it might well provide an alternative and more convenient administration regimen.

    In its submissions Merial provided a table identifying the WO’115 disclosure relevant to the claims. Relying on that information I am satisfied that WO’115 discloses the additional features of opposed claims 3-20, such that in seeking to solve the problem using the WO’115 disclosure, the person skilled in the art would directly be led as a matter of course to try the additional subject matter encompassed by these claims with a reasonable expectation that it might well solve the problem.”

  13. Merial submitted that the claims as amended lack an inventive step in view of the findings in the earlier decision.  That is, each of the features of the amended claims can be identified in a claim I found to be lacking an inventive step in the earlier decision (referring in particular to the finding of lack of inventive step in relation to accepted claims 4-6, 15 and 17).  To the extent that there is a gap between the findings of the earlier decision and the amended claims, Merial submitted that WO’115 brings together the features of the claims, or, as a secondary position, the features are part of the common general knowledge.  In the context of the construction of the amended claims as requiring simultaneous efficacy against all the included antigens, Merial submitted that the specification provides no evidence of any unexpected simultaneous efficacy.

  14. Zoetis submitted that the earlier decision made no finding on the specifically claimed combinations, and that no inferences can be drawn from what was decided earlier unless supported by the evidence.  Zoetis submitted that the finding at [119] of the earlier decision relates only to each of the antigens separately, or the combination provided in WO’115, which in Zoetis’ submission is limited to a Bordatella bronchiseptica p68 antigen with at least one other canine antigen including CCV.  Accordingly, Zoetis submitted that WO’115 does not specifically relate to the combination of four antigens that are the subject of amended claims 1 and 2, and there is no finding that a skilled person would be motivated to try oral dosing of the claimed combinations.

  15. Further, Zoetis submitted that it cannot be concluded from the earlier decision that a skilled person would be directly led as a matter of course to the invention defined in the amended claims with the requisite expectation of success that the combination of antigens would be therapeutically effective against all four diseases (i.e. canine distemper, canine adenovirus, canine parainfluenza and canine parvovirus) when given in the specifically defined dosing regimen.  In particular, Zoetis submitted that the possibility of immunogenic interference, which might differ when the antigens are administered orally versus subcutaneously, and which might be time dependent, were relevant factors in considering the required expectation of success.  In this regard Zoetis referred to Zwisler et al. (Exhibit REB-19) which indicates that orally delivered antigens may be attacked by digestive enzymes, as well as a passage of WO’115:

    “A problem in developing combination vaccines involves efficacy interference, namely a failure of one or more antigens in a combination composition to maintain or achieve efficacy because of the presence of other antigens in the composition.  This is believed to be a result of interference with an antigen in the composition administered to a host, e.g. a dog, in the immunological, antigenic, antibody or protective response such antigen induced in the host because of the other antigens present in the composition.  However, for other hosts, such as cats, combination vaccines are known.  It is believed that efficacy interference in dogs is due to some peculiarity of the canine biological system, or due to the reaction of the antigens with the canine biological system.” (page 2, line 42 – page 3, line 11)

  16. It is clearly important to understand what was decided in the earlier decision, and I consider this to include both my ultimate conclusions in relation to the inventiveness of the claims, but also the findings on which those conclusions are based.  This is, in my view, consistent with the observation in  R v Smith; Ex parte Mole Engineering Pty Ltd [1981] HCA 25; (1981) 147 CLR 340 at 358, that an interim decision “provides a firm base on which another officer can proceed in the exercise of the powers of the Commissioner.”

  17. While none of the claims as accepted include all the integers of the amended claims, and I therefore made no explicit finding with regard to that combination of integers, I found in the earlier decision at [119] that “administering the core canine vaccine antigens or combinations of antigens identified in WO’115, in 2-3 doses followed by one or more annual boosters, all orally or in a combination of one or two subcutaneous doses followed by oral doses” was not inventive in light of WO’115, and accordingly I found that accepted claims 4-6, which define combinations of four to five canine antigens and a bacterin lacked inventive step. As noted above, the accepted claims define combinations encompassed by amended claims 1 and 2, and I consider that the construction adopted for the amended claims as discussed at [9] above necessarily also applies to the accepted claims where they define combinations of antigens. It follows that insofar as Zoetis’ argument relies on a failure of WO’115 to disclose such antigen combinations, or a lack of expectation of success associated with the possibility of immunogenic interference associated with oral administration of those combinations, that argument cannot succeed.

  18. In the earlier decision, I found that oral administration, or a combination of oral and subcutaneous administration, of the antigen combinations defined in the amended claims lacks an inventive step; that is, a skilled person would be directly led to try these routes or combination of routes with a reasonable expectation of arriving at an alternative and more convenient administration regimen.  Therefore, it is not now open to me to decide otherwise.  However, relevant to the passage that Zoetis relies on in WO’115 regarding immunogenic interference, I note that the subsequent paragraphs indicate that this is a problem addressed by the WO’115 disclosure.

  19. The question to be decided, having established in the earlier decision that administration of the presently claimed combinations of antigens lacks inventive step, is whether a skilled worker would directly be led as a matter of course to the specific dosing intervals defined in the amended claims with a reasonable expectation of arriving at an alternative and more convenient administration regimen for a combination canine vaccine. 

  20. In the earlier decision at [105], I found that a skilled worker would consider both preferred embodiments and other options in WO’115 in seeking to provide an alternative and more convenient administration regimen for canine vaccines:

    “In my view it is not reasonable to necessarily read down the WO’115 disclosure to that which forms the common general knowledge in the art or the preferred embodiments.  The person skilled in the art is seeking to provide an alternative and more convenient administration regimen for canine vaccines.  Consequently, it is reasonable to expect that they would consider not only the preferred embodiments in a prior disclosure, but also any other options that could be applied to solve the problem.”

  21. Accordingly, in the earlier decision at [120], I found that claims 15 and 17, which specify administration of a second vaccine dose from 7 to 35 days after the first dose and administration of a third vaccine dose from 7 to 35 days after the second dose, respectively, lacked inventive step in light of WO’115 on the basis that WO’115 disclosed the claimed dosing regimen.  Relevantly, WO’115 discloses vaccination schedules falling within the scope of those defined in the amended claims:

    “The combination vaccines can be administered in 2 to 4 doses, preferably in 2 to 3 doses. The doses can be administered with 2 to 6 weeks between each dose, preferably with 2 to 4 weeks between each dose.

    The administration can be done by any known routes, including the oral, intranasal, mucosal topical, transdermal, and parenteral …” (WO’115, page 13, lines 11-15)

    “In accordance with the present invention, the p68/5CV, p68/5CV-Leptospira, 5CV, 5CV-5Leptospira, 5CV-4Leptospira, and 5CV-2Leptospira combination vaccines can be administered to healthy dogs … preferably in 3 doses, each administered about 3 weeks apart. Dogs can be revaccinated annually with a single dose.” (WO’115, page 14, lines 29-33)

  22. While I made no explicit finding in relation to the amended claims, it is clear that the combination of features they contain is disclosed in WO’115, and I found in the earlier decision at [119] that a skilled addressee

    “… would directly be led as a matter of course to try treating a dog for canine diseases by administering the core canine vaccine antigens or combinations of antigens identified in WO’115, in 2-3 doses followed by one or more annual boosters, all orally or in a combination of one or two subcutaneous doses followed by oral doses, with a reasonable expectation that it might well provide an alternative and more convenient administration regimen.” 

  23. The antigen combinations taught by WO’115 encompass those defined in the amended claims (that is, page 13 of WO’115 indicates that CV5 denotes a combination of CD, CAV-2, CPI, CPV and CCV antigens).  This is consistent with my finding that accepted claims 4-6 lack inventive step in light of this document.  Having decided that a skilled addressee would administer the combinations of antigens identified in WO’115 in 2-3 doses, it is a logical conclusion that they would do so in the manner instructed by WO’115.

  24. The parties have not drawn my attention to, and I have not identified, anything in the evidence that explicitly addresses specific dosing intervals for the presently claimed combination vaccine when administered either in all oral doses or in a combination of oral and subcutaneous doses.  However, the dosing intervals disclosed in WO’115 accord with what Mr Bevan and Dr Holloway understand to be usual in the art in relation to subcutaneous dosing intervals.  That is, Mr Bevan indicated that he would routinely vaccinate puppies at 6, 10 and 12-13 weeks (as per manufacturer’s instructions), and Dr Holloway at 6-8, 10-12 and 14-16 weeks (Bevan#1 at [9]; Holloway#1 at [4(p)], [4](u)]).  Additionally, Mr Bevan’s evidence in relation to a single component vaccine, which I relied on in the earlier decision, is that the dosing intervals for injectable vaccines could be adopted for oral vaccinations (Bevan#2 at [17]).   This is consistent with his observation that:

    “… multiple dosing of antigens (including the antigens described in the Opposed Application) was already described in REB-16 (WO 2006/038115) and already existed in practice, and further, as evidenced in documents described below, previous studies had demonstrated the success of oral vaccination of dogs. These factors all suggest to me that oral vaccination was certainly feasible and I would have expected it to succeed.” (Bevan#2 at [16])

  1. Insofar as Mr Bevan considers that WO’115 discloses multiple dosing I consider that it is reasonable to infer that he is referring to multiple dosing as disclosed therein, including the disclosed intervals, and expects that such dosing intervals would succeed in the context of oral vaccination with the antigens disclosed in the present application.  Therefore, the available evidence is consistent with the logical extrapolation of the earlier decision to follow the express disclosure of WO’115.  This is also consistent with my finding at [117] of the earlier decision that:

    “It is reasonable to conclude that regardless of the route of administration, the person skilled in the art would directly be led as a matter of course to administer core canine vaccine antigens in accordance with the common general knowledge in the art; that is in 2-3 doses followed by one or more yearly boosters.”

  2. While Zoetis raised the question of whether there might be time-dependent interactions associated with oral administration of combination vaccines, they did not point to any evidence of that prospect engendering a lack of expectation of success in a skilled person.  WO’115 expressly discloses dosing schedules in accordance with those defined in the amended claims, and in the absence of evidence, I am not persuaded that any potential there may be for unwanted interactions during oral administration is such that it would prevent the skilled addressee having a reasonable expectation of success in trying the dosing schedule disclosed.  It follows that I do not consider that amended claims 1 and 2 have overcome the inventive step finding in the earlier decision.

  3. The features of appended claims 3-19 substantially reflect those of the claims as accepted, and therefore as previously identified in the earlier decision at [120], they recite features which are disclosed by WO’115, such that in seeking to solve the problem using the WO’115 disclosure, the person skilled in the art would be directly led as a matter of course to try the additional subject matter encompassed by these claims with a reasonable expectation that it might well solve the problem.

    Baer

  4. My finding in relation to Baer is summarised at [138]-[140] of the earlier decision as follows:

“On balance, I am satisfied that in all the circumstances, the person skilled in the art would directly be led as a matter of course to try oral administration of the CAV-2 antigen taught by Baer, in accordance with the common general knowledge in the art, i.e. by vaccinating two or three times, followed by annual booster vaccinations, with a reasonable expectation that it might well produce a more convenient vaccine regimen. It follows that the subject matter of claim 1 lacks an inventive step.

The subject matter of dependent claim 7, insofar as it encompasses the method wherein the canine disease comprises respiratory disease caused by CAV-2, is also obvious in light of Baer. I also consider the dosing schedules in dependent claims 15, 17-20 obvious in light of Mr Bevan’s evidence above, that these dosing schedules were a matter of routine.

I find claims 1, 7, 15 and 17-20 do not involve an inventive step in light of Baer.”

  1. Merial submitted that Baer, taken together with common general knowledge, remains relevant to amended claim 1.  However, in the earlier decision I found that claims directed to a combination of canine antigens were not obvious in light of Baer (that is, I did not find that accepted claims 3-6 lacked inventive step in light of Baer).  This final determination is not an opportunity to re-open the earlier decision on this point.  Accordingly, as the amended claims are limited to combinations of canine antigens, the amendments overcome the inventive step finding in relation to Baer.

    Conclusion

  2. I have found that the amendments do not overcome the inventive step deficiencies identified in the earlier decision.  This raises the question of whether Zoetis should be given a further opportunity to amend.  I consider that Zoetis has made a genuine attempt to overcome the deficiencies identified in the earlier decision, and there may be subject matter disclosed in the specification that would overcome the defects identified in this and the earlier decision.  Therefore, I will allow Zoetis a further short period in which to file further amendments to the claims. 

    Costs

  3. Neither party made submissions on costs.  It is normal in matters before the Commissioner that costs should follow the event.  Merial has been successful in this matter, and therefore I will award costs according to Schedule 8 against Zoetis.

    Barbara Akhurst
    Delegate of the Commissioner of Patents

    Annex A: The accepted claims (the subject of the earlier decision)

    1. A method of treating a dog for canine diseases comprising administering to the dog therapeutically effective amounts of vaccine, wherein the vaccine comprises viral antigens, a bacterin, or both, and wherein the vaccine is administered subcutaneously or orally in a first dose, orally in a second dose, orally in an optional third dose, and orally in one or more annual doses, and wherein the viral antigens comprise one or more of 1) canine distemper (CD) virus, 2) canine adenovirus type 2 (CAV-2), 3) canine parainfluenza (CPI) virus, 4) canine parvovirus (CPV), 5) and canine coronavirus (CCV), and wherein the bacterin comprises one or more bacteria selected from Leptospira canicola, L. grippotyphosa, L. icterohaemorrhagiae, L. pomona, L. bratislava, and Bordetella bronchiseptica; and any combination of viral antigens and bacteria thereof.

    2. A method of treating a dog for canine diseases comprising administering to the dog therapeutically effective amounts of vaccine, wherein the vaccine comprises viral antigens, a bacterin, or both, and wherein the vaccine is administered subcutaneously in a first and in a second dose, and orally in a third dose, and orally in one or more annual doses, and wherein the viral antigens comprise one or more of 1) CD virus, 2) CAV-2, 3) CPI virus, 4) CPV, 5) and CCV, and the bacterin comprises one or more bacteria selected from Leptospira canicola, L. grippotyphosa, L. icterohaemorrhagiae, L. pomona, L. bratislava, and Bordetella bronchiseptica; and any combination of viral antigens and bacteria thereof.

    3. A method according to claims 1 or 2, wherein the viral antigens are CD virus, CAV-2, CPI virus, and CPV.

    4. A method according to claims 1 or 2, wherein the viral antigens are CD virus, CAV-2, CPI virus, and CPV, and the bacteria in the bacterin are Leptospira canicola, L. grippotyphosa, L. icterohaemorrhagiae, and L. pomona.

    5. A method according to claims 1 or 2, wherein the viral antigens are CD virus, CAV-2, CPI virus, CPV, and CCV, and the bacteria in the bacterin are Leptospira canicola, L. grippotyphosa, L. icterohaemorrhagiae, and L. pomona.

    6. A method according to claims 1 or 2, wherein the viral antigens are CD virus, CAV-2, CPI virus, and CPV, and the bacterium in the bacterin is Bordetella bronchiseptica.

    7. A method according to claims 1 or 2, wherein the canine diseases comprise one or more of 1) CD caused by CD virus; 2) infectious canine hepatitis caused by CAV-1; 3) respiratory disease caused by CAV-2 or respiratory CCV; 4) CPI caused by CPI virus; 5) enteritis caused by CCV or CPV; 6) leptospirosis caused by Leptospira canicola, L. grippotyphosa, L. icterohaemorrhagiae, L. pomona, or L. Bratislava; and 7) infectious tracheobronchitis ("kennel cough") caused by Bordetella bronchiseptica.

    8. A method according to claim 7, wherein the diseases comprise 1) CD caused by CD virus; 2) infectious canine hepatitis caused by CAV-1; 3) respiratory disease caused by CAV-2; 4) CPI caused by CPI virus; 5) and canine parvoviral enteritis caused by CPV.

    9. A method according to claims 1 or 2, wherein the viral antigens are present in the following ranges of amounts: for CD virus, about 102 TCID50 to about 108 TCID50, inclusive; for CAV-2, about 102 TCID50 to about 108 TCID50, inclusive; for CPV, about 103 TCID50 to about 1010 TCID50, inclusive; for CPI virus, about 103 TCID50 to about 1010 TCID50, inclusive; and for CCV, at least about 100 relative units (RU) per dose.

    10. A method according to claims 1 or 2, wherein the viral antigens are present in the following ranges of amounts: for CD virus, about 103 TCID50 to about 106 TCID50, inclusive; for CAV-2, about 103 TCID50 to about 106 TCID50, inclusive; for CPV, about 106 TCID50 to about 109 TCID50, inclusive; for CPI virus, about 105 TCID50 to about 109 TCID50, inclusive; and for CCV, about 1,000 RU to about 4,500 RU per dose

    11. A method according to claims 1 or 2, wherein the viral antigens are present in the following ranges of amounts: for CD virus, about 104 TCID50 to about 105 TCID50, inclusive; for CAV-2, about 104 TCID50 to about 105 TCID50, inclusive; for CPV, about 107 TCID50 to about 108 TCID50, inclusive; and for CPI virus, about 106 TCID50 to about 108 TCID50, inclusive.

    12. A method according to claims 1 or 2, wherein each Leptospira is present in a range of amounts from about 100 nephelometric units (NU) to about 3,500 NU per vaccine dose, and wherein the Bordetella bronchiseptica is present in a range from about 3 x 106 to about 3 x 1011 cells inclusive.

    13. A method according to claims 1 or 2, wherein each Leptospira is present in a range of amounts from about 200 NU to about 2,000 NU per dose, and wherein the Bordetella bronchiseptica is present in a range from about from about 3 x 107 to about 3 x 1010 cells inclusive.

    14.A method according to claims 1 or 2, wherein the Bordetella bronchiseptica is present in a range from about 3 x 108 to about 3 x 109 cells inclusive.

    15.A method according to claims 1 or 2, wherein the second dose is administered from 7 to 35 days, inclusive, after the first dose.

    16. A method according to claim 15, wherein the second dose is administered about 3 weeks after the first dose.

    17. A method according to claims 1 or 2, wherein the third dose is administered from 7 to 35 days, inclusive, after the second dose.

    18. A method according to claim 17, wherein the third dose is administered about 3 weeks after the second dose.

    19.A method according to claims 1 or 2, wherein the annual dose is administered about one year after the first dose.

    20. A method according to claim 19, wherein annual doses administered after said annual dose are administered repeatedly about one year after the immediately prior annual dose.

    Annex B: The amended claims

    1. A method of treating a dog for canine diseases comprising administering to the dog therapeutically effective amounts of a vaccine; wherein the vaccine comprises viral antigens and a bacterin;

    wherein the viral antigens comprise 1) canine distemper (CD) virus, 2) canine adenovirus type 2 (CAV-2), 3) canine parainfluenza (CPI) virus, and 4) canine parvovirus (CPV);
    wherein the bacterin comprises one or more bacteria selected from Leptospira canicola, L. grippotyphosa, L. icterohaemorrhagiae, L. pomona, L. bratislava, and Bordetella bronchiseptica;
    wherein the vaccine is administered orally in a first dose, orally in a second dose, orally in a third dose, and orally in one or more annual doses;
    wherein the second dose is administered from 7 to 35 days, inclusive, after the first dose; and
    wherein the third dose is administered from 7 to 35 days, inclusive, after the second dose.

    2. A method of treating a dog for canine diseases comprising administering to the dog therapeutically effective amounts of a vaccine; wherein the vaccine comprises viral antigens and a bacterin;

    wherein the viral antigens comprise 1) canine distemper (CD) virus, 2) canine adenovirus type 2 (CAV-2, 3) canine parainfluenza (CPI) virus, and 4) canine parvovirus (CPV);
    wherein the bacterin comprises one or more bacteria selected from Leptospira canicola, L. grippotyphosa, L. icterohaemorrhagiae, L. pomona, L. bratislava, and Bordetella bronchiseptica;
    wherein the vaccine is administered subcutaneously in a first dose, orally or subcutaneously in a second dose, orally in a third dose, and orally in one or more annual doses;
    wherein the second dose is administered from 7 to 35 days, inclusive, after the first dose; and
    wherein the third dose is administered from 7 to 35 days, inclusive, after the second dose.

    3. The method of claim 1 or 2, wherein the vaccine further comprises canine coronavirus (CCV).

    4. The method according to claim 1 to 3, wherein the bacteria in the bacterin are Leptospira canicola, L. grippotyphosa, L. icterohaemorrhagiae, and L. pomona.

    5. The method according to any one of claims 1 to 3, wherein the bacterium in the bacterin is Bordetella bronchiseptica.

    6. The method according to claims 1 to 3, wherein the canine diseases comprise one or more of 1) CD caused by CD virus; 2) infectious canine hepatitis caused by CAV-1; 3) respiratory disease caused by CAV-2 or respiratory CCV; 4) CPI caused by CPI virus; 5) enteritis caused by CCV or CPV; 6) leptospirosis caused by Leptospira canicola, L. grippotyphosa, L. icterohaemorrhagiae, L. pomona, or L. Bratislava; and 7) infectious tracheobronchitis ("kennel cough") caused by Bordetella bronchiseptica.

    7. The method according to claim 6, wherein the canine diseases comprise 1) CD caused by CD virus; 2) infectious canine hepatitis caused by CAV-1; 3) respiratory disease caused by CAV-2; 4) CPI caused by CPI virus; 5) and canine parvoviral enteritis caused by CPV.

    8. The method according to any one of claims 1 to 3, wherein the viral antigens are present in the following ranges of amounts: for CD virus, about 102 TCID50 to about 108 TCID50, inclusive; for CAV-2, about 102 TCID50 to about 108 TCID50, inclusive; for CPV, about 103 TCID50 to about 1010 TCID50, inclusive; for CPI virus, about 103 TCID50 to about 1010 TCID50, inclusive; and for CCV, at least about 100 relative units (RU) per dose.

    9. The method according to any one of claims 1 to 3, wherein the viral antigens are present in the following ranges of amounts: for CD virus, about 103 TCID50 to about 106 TCID50, inclusive; for CAV-2, about 103 TCID50 to about 108 TCID50, inclusive; for CPV, about 106 TCID50 to about 109 TCID50, inclusive; for CPI virus, about 105 TCID50 to about 109 TCID50, inclusive; and for CCV, about 1,000 RU to about 4,500 RU per dose

    10. The method according to any one of claims 1 to 3, wherein the viral antigens are present in the following ranges of amounts: for CD virus, about 104 TCID50 to about 105 TCID50, inclusive; for CAV-2, about 104 TCID50 to about 105 TCID50, inclusive; for CPV, about 107 TCID50 to about 108 TCID50, inclusive; and for CPI virus, about 106 TCID50 to about 108 TCID50, inclusive.

    11. The method according to any one of claims 1 to 3, wherein each Leptospira is present in a range of amounts from about 100 nephelometric units (NU) to about 3,500 NU per vaccine dose, and wherein the Bordetella bronchiseptica is present in a range from about 3 x 106 to about 3 x 1011 cells inclusive.

    12. The method according to any one of claims 1 to 3, wherein each Leptospira is present in a range of amounts from about 200 NU to about 2,000 NU per dose, and wherein the Bordetella bronchiseptica is present in a range from about from about 3 x 107 to about 3 x 1010 cells inclusive.

    13. The method according to any one of claims 1 to 3, wherein the Bordetella bronchiseptica is present in a range from about 3 x 108 to about 3 x 109 cells inclusive.

    14. The method according to any one of claims 1 to 3, wherein the second dose is administered about 3 weeks after the first dose.

    15. The method according to any one of claims 1 to 3, wherein the third dose is administered about 3 weeks after the second dose.

    16. The method according to any one of claims 1 to 3, wherein the annual dose is administered about one year after the first dose.

    17. The method according to claim 16, wherein annual doses administered after the annual dose are administered repeatedly about one year after the immediately prior annual dose.

    18. The method according to claim 2 or 3, wherein the second dose is administered orally.

    19. The method according to claim 2 or 3, wherein the second dose is administered subcutaneously.

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